Prodrug salts

ABSTRACT

Provided are novel prodrug salts of selective aquaporin inhibitors, their use as pharmaceuticals, and pharmaceutical compositions comprising them, and novel processes for their synthesis and novel intermediates for use in their synthesis. Also provided is use of a compound for the prophylaxis, treatment, and control of aquaporin-mediated conditions. Aquaporin inhibitors, e.g., inhibitors of AQP4 and/or AQP2, may be of utility in the treatment or control of diseases of water imbalance, for example edema (particularly edema of the brain and spinal cord), hyponatremia, and excess fluid retention, as well as diseases such as epilepsy, retinal ischemia and other diseases of the eye, myocardial ischemia, myocardial ischemia/reperfusion injury, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, and neuromyelitis optica, as well as migraines.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/296,663 filed Mar. 8, 2019, now abandoned, which is a continuation ofU.S. patent application Ser. No. 15/792,707 filed Oct. 24, 2017, nowissued as U.S. Pat. No. 10,258,636, which is a divisional of U.S. patentapplication Ser. No. 15/034,274 filed May 4, 2016, now issued as U.S.Pat. No. 9,827,253, which is the National Stage Entry under 35 U.S.C. §371 of International Application No. PCT/US2014/064447 filed Nov. 6,2014, which claims priority to U.S. Provisional Application No.61/900,878 filed Nov. 6, 2013, U.S. Provisional Application No.61/900,919 filed Nov. 6, 2013, and U.S. Provisional Application No.61/900,946 filed Nov. 6, 2013, the contents of each of which areincorporated herein by reference.

TECHNICAL FIELD

Provided are novel prodrug salts of selective aquaporin inhibitors,e.g., of aquaporin-4 and/or aquaporin-2, of Formula I as describedbelow, their use as pharmaceuticals and pharmaceutical compositionscomprising them, and novel intermediates used in and novel processes fortheir synthesis. These novel prodrug salts are useful e.g., in theprophylaxis, treatment, and control of aquaporin-mediated conditions,e.g., diseases of water imbalance, for example edema (particularly edemaof the brain and spinal cord, e.g., following trauma or ischemic stroke,as well as edema associated with glioma, meningitis, acute mountainsickness, epileptic seizure, infection, metabolic disorder, hypoxia,water intoxication, hepatic failure, hepatic encephalopathy, diabeticketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob disease, and lupuscerebritis, as well as edema consequent to microgravity and/or radiationexposure, as well as optic nerve edema, e.g., optic nerve edemaconsequent to microgravity and/or radiation exposure, as well as edemaconsequent to an invasive central nervous system procedure, e.g.,neurosurgery, endovascular clot removal, spinal tap, aneurysm repair, ordeep brain stimulation, as well as retinal edema, as well as pulmonaryedema, as well as brain swelling consequent to cardiac arrest, e.g.,related to the development of the metabolic acidosis (e.g. lacticacidosis) due to hypoxia before the resuscitation period), as well ashyponatremia and excess fluid retention, ovarian hyperstimulationsyndrome, and diseases such as epilepsy, retinal ischemia and otherdiseases of the eye associated with abnormalities in intraocularpressure and/or tissue hydration, myocardial ischemia, myocardialischemia/reperfusion injury, myocardial infarction, myocardial hypoxia,congestive heart failure, sepsis, neuromyelitis optica, andglioblastoma, as well as fibromyalgia, multiple sclerosis, andmigraines.

BACKGROUND

Aquaporins are cell membrane proteins that act as molecular waterchannels to mediate the flow of water in and out of the cells. Whilethere is some degree of passive diffusion or osmosis of water acrosscell membranes, the rapid and selective transport of water in and out ofcells involves aquaporins. These water channels selectively conductwater molecules in and out of the cell, while blocking the passage ofions and other solutes, thereby preserving the membrane potential of thecell. Aquaporins are found in virtually all life forms, from bacteria toplants to animals. In humans, they are found in cells throughout thebody.

Aquaporin inhibitors, e.g., inhibitors of AQP4 and/or AQP2, may be ofutility in the treatment or control of diseases of water imbalance, forexample edema (particularly edema of the brain and spinal cord),hyponatremia, and excess fluid retention, as well as diseases such asepilepsy, retinal ischemia and other diseases of the eye, myocardialischemia, myocardial ischemia/reperfusion injury, myocardial infarction,myocardial hypoxia, congestive heart failure, sepsis, and neuromyelitisoptica, as well as migraines.

Prior to Applicants' filings, there have been no known specific,validated inhibitors of aquaporins, for example AQP4 or AQP2. Certainantiepileptic or sulfonamide drugs (e.g., acetylsulfanilamide,acetazolamide, 6-ethoxy-benzothiazole-2-sulfonamide, topiramate,zonisamide, phenytoin, lamotrigine, and sumatriptan) were at one pointreported to be possible inhibitors of AQP4, but this later proved to beincorrect. Yang, et al., Bioorganic & Medicinal Chemistry (2008) 16:7489-7493. No direct inhibitors of AQP2 have been reported.

Thus, there is a need for compounds that selectively inhibit aquaporins.In addition, there is a need for compounds that may be formulated todeliver compounds that selectively inhibit aquaporins, for examplecompounds which may be soluble in aqueous media and/or may beadministered easily to patients.

BRIEF SUMMARY

Provided is a compound of Formula I

wherein:R¹, R², R³, R⁴, and R⁵ are independently H, halogen (e.g., Cl or Br),C₁₋₄-alkyl, C₁₋₄-haloalkyl (e.g., —CF₃), or cyano;one of R⁶ and R⁷ is OH and the other is O⁻Q⁺ or both of R⁶ and R⁷ areO⁻Q⁺;each Q+ is independently Na⁺, K⁺, HOR⁸NH₃ ⁺, (HOR⁸)₂NH₂ ⁺, or(HOR⁸)₃NH⁺; andeach R⁸ is independently C₁₋₄-alkylene (e.g., —CH₂—CH₂—).

Also provided is a compound of Formula I which is a compound of FormulaII

wherein:one of R⁶ and R⁷ is OH and the other is O⁻Q⁺ or both of R⁶ and R⁷ areO⁻Q⁺;each Q⁺ is independently K⁺, HOR⁸NH₃ ⁺, (HOR⁸)₂NH₂ ⁺, or (HOR⁸)₃NH⁺; andeach R⁸ is independently C₁₋₄-alkylene (e.g., —CH₂—CH₂—).

Also provided is a pharmaceutical composition comprising a compound ofFormula I, e.g., a compound of Formula II, and a pharmaceuticallyacceptable excipient.

Also provided is use of a compound of Formula I, e.g., a compound ofFormula II, for the prophylaxis, treatment, and control ofaquaporin-mediated conditions, e.g., diseases of water imbalance, forexample edema (particularly edema of the brain and spinal cord, e.g.,following trauma or ischemic stroke, as well as edema associated withglioma, meningitis, acute mountain sickness, epileptic seizure,infection, metabolic disorder, hypoxia, water intoxication, hepaticfailure, hepatic encephalopathy, diabetic ketoacidosis, abscess,eclampsia, Creutzfeldt-Jakob disease, and lupus cerebritis, as well asedema consequent to microgravity and/or radiation exposure, as well asoptic nerve edema, e.g., optic nerve edema consequent to microgravityand/or radiation exposure, as well as edema consequent to an invasivecentral nervous system procedure, e.g., neurosurgery, endovascular clotremoval, spinal tap, aneurysm repair, or deep brain stimulation, as wellas retinal edema, as well as brain swelling consequent to cardiacarrest, e.g., related to the development of the metabolic acidosis (e.g.lactic acidosis) due to hypoxia before the resuscitation period), aswell as hyponatremia and excess fluid retention, ovarianhyperstimulation syndrome, as well as diseases such as epilepsy, retinalischemia and other diseases of the eye associated with abnormalities inintraocular pressure and/or tissue hydration, myocardial ischemia,myocardial ischemia/reperfusion injury, myocardial infarction,myocardial hypoxia, congestive heart failure, sepsis, neuromyelitisoptica, and glioblastoma, as well as migraines.

Also provided is a method of treating or controlling a disease orcondition mediated by an aquaporin, e.g., diseases or conditions ofwater imbalance and other diseases, for example,

-   -   edema of the brain or spinal cord, e.g., cerebral edema, e.g.        cerebral edema consequent to head trauma, ischemic stroke,        glioma, meningitis, acute mountain sickness, epileptic seizure,        infection, metabolic disorder, hypoxia (including general        systemic hypoxia and hypoxia due to cardiac arrest), water        intoxication, hepatic failure, hepatic encephalopathy, diabetic        ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob disease,        lupus cerebritis, cardiac arrest, microgravity and/or radiation        exposure, or an invasive central nervous system procedure, e.g.,        neurosurgery, endovascular clot removal, spinal tap, aneurysm        repair, or deep brain stimulation or, e.g., spinal cord edema        consequent to spinal cord trauma, e.g., spinal cord compression;        or    -   optic nerve edema, e.g., optic nerve edema consequent to        microgravity and/or radiation exposure; or    -   retinal edema; or    -   hyponatremia or excessive fluid retention, e.g., consequent to        heart failure (HF), liver cirrhosis, nephrotic disorder,        syndrome of inappropriate antidiuretic hormone secretion        (SIADH), or infertility treatment; or    -   ovarian hyperstimulation syndrome; or    -   epilepsy, retinal ischemia or other diseases of the eye        associated with abnormalities in intraocular pressure and/or        tissue hydration, myocardial ischemia, myocardial        ischemia/reperfusion injury, myocardial infarction, myocardial        hypoxia, congestive heart failure, sepsis, neuromyelitis optica,        or glioblastoma;    -   or migraines,        comprising administering to a patient in need thereof a        therapeutically effective amount of a compound of Formula I,        e.g., a compound of Formula II.

Also provided is a compound of Formula III

wherein:R³⁰, R³¹, R³², R³³, and R³⁴ are independently H, halogen (e.g., Cl orBr), C₁₋₄-alkyl, C₁₋₄-haloalkyl (e.g., —CF₃), or cyano; andR³⁵ and R³⁶ are independently protecting groups, e.g., wherein R³⁵ andR³⁶ are independently a protecting group comprising Si, S, N, and/or O,e.g., wherein R³⁵ and R³⁶ are independently a protecting groupcomprising an optionally substituted cyclic or acyclic ether, anoptionally substituted silyl (e.g., —Si(C₁₋₆-alkyl)₃, e.g.,—Si(C₁₋₄-alkyl)₃, e.g., —Si(CH₃)₃), an optionally substituted silylether, an optionally substituted ester, an optionally substitutedketone, or an optionally substituted thioether, e.g., wherein R³⁵ andR³⁶ are independently —CH₂OR′, —CH₂SR′,

—C(OC₁₋₆-alkyl)(R′)₂, —CH(R′)OR′, —C(R′)₃, —Si(R″)₃, —C(O)R″, or—C(O)OR″, wherein each R′ is independently H, C₁₋₆-alkyl (e.g.,C₁₋₄-alkyl), —CH₂Si(R″)₃, —CH₂-Aryl (e.g., phenyl), —C₁₋₆-alkenyl,—CH₂OSi(R″)₃, alkoxyalkyl, or —CH₂CH₂Si(R″)₃ and each R″ isindependently C₁₋₆-alkyl (e.g., C₁₋₄-alkyl) or aryl optionallysubstituted with alkoxy (e.g., —C₁₋₆-alkoxy, e.g., —C₁₋₄-alkoxy),halogen, cyano, or aryl (e.g., phenyl), wherein each R′ is optionallysubstituted with alkyl, alkoxyalkyl, or aryl, e.g.,—(CH₂CH₂)_(n)—Si(R³⁷)₃), wherein each R³⁷ is independently C₁₋₆-alkyl,e.g., C₁₋₄-alkyl and n is 0 or 1,and wherein R³⁵ and R³⁶ are not both —CH₂—C₆H₅.

Also provided is a compound of Formula XX

wherein:R⁴⁰ and R⁴¹ are independently protecting groups, e.g., wherein R⁴⁰ andR⁴¹ are independently a protecting group comprising Si, S, N, and/or O,e.g., wherein R⁴⁰ and R⁴¹ are independently a protecting groupcomprising an optionally substituted cyclic or acyclic ether, anoptionally substituted silyl (e.g., —Si(C₁₋₆-alkyl)₃, e.g.,—Si(C₁₋₄-alkyl)₃, e.g., —Si(CH₃)₃), an optionally substituted silylether, an optionally substituted ester, an optionally substitutedketone, or an optionally substituted thioether, e.g., wherein R⁴⁰ andR⁴¹ are independently —CH₂OR′, —CH₂SR′,

—C(OC₁₋₆-alkyl)(R′)₂, —CH(R′)OR′, —C(R′)₃, —Si(R″)₃, —C(O)R″, or—C(O)OR″, wherein each R′ is independently H, C₁₋₆-alkyl (e.g.,C₁₋₄-alkyl), —CH₂Si(R″)₃, —CH₂-Aryl (e.g., phenyl), —C₁₋₆-alkenyl,—CH₂OSi(R″)₃, alkoxyalkyl, or —CH₂CH₂Si(R″)₃ and each R″ isindependently C₁₋₆-alkyl (e.g., C₁₋₄-alkyl) or aryl optionallysubstituted with alkoxy (e.g., —C₁₋₆-alkoxy, e.g., —C₁₋₄-alkoxy),halogen, cyano, or aryl (e.g., phenyl), wherein each R′ is optionallysubstituted with alkyl, alkoxyalkyl, or aryl, e.g.,—(CH₂CH₂)_(n)—Si(R³⁷)₃), wherein each R³⁷ is independently C₁₋₆-alkyl,e.g., C₁₋₄-alkyl and n is 0 or 1,and wherein R⁴¹ and R³⁴¹ are not both —CH₂—C₆H₅.

Also provided is a process for synthesizing a compound of Formula I,e.g., a compound of Formula II, comprising reacting a compound ofFormula III and/or Formula XX.

Also provided is a process for synthesizing a compound of Formula III.

Further areas of applicability of the present disclosure will becomeapparent from the detailed description provided hereinafter. It shouldbe understood that the detailed description and specific examples, whileindicating the preferred embodiment of the disclosure, are intended forpurposes of illustration only and are not intended to limit the scope ofthe disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts results of aquaporin-4 (FIG. 1A) and aquaporin-2 (FIG.1B) mediated cell volume change assay, and the inhibitory effect of5-chloro-N-(3,5-dichlorophenyl)-2-hydroxybenzamide (Compound 3) againstthese aquaporins.

FIG. 2 depicts specificity of5-chloro-N-(3,5-dichlorophenyl)-2-hydroxybenzamide (Compound 3) towardsAQP-1, AQP-2, AQP-4-M1, AQP-4-M23, and AQP-5.

FIG. 3 depicts a Hummel-Dryer style assay for [3H]-labeledN-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxy-5-(trifluoromethyl)benzamide(Compound 4) binding to purified AQP4b.

FIG. 4 depicts percent survival curves for the water toxicity mousemodel using 0.76 mg/kgN-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Compound1).

FIG. 5 depicts inhibition of cerebral edema formation byN-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide(Compound 1) in the mouse water toxicity model by MRI brain volumeanalysis, with n=14 mice/treatment. A time course of edema formation isshown comparing no drug vs.N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide(Compound 1) at 0.76 mg/kg. The first time point at 5.67 min coincideswith the scan slice at the middle of the brain during the firstpost-injection scan. Other time points are placed in a similar manner.The data is fitted to a single exponential equation:V/V ₀ =V _(i) +dV _(max)(1−e ^((−kt)));

-   -   where V/V₀=relative brain volume, V_(i)=initial relative brain        volume, dV_(max)=maximum change in relative brain volume,        k=first order rate constant (min⁻¹), and t=time in minutes.

FIG. 6 depicts the calcein fluorescence end-point assay used for highthroughput screening.

FIG. 7 depicts hit validation using the Cell Bursting Aquaporin Assay;inset shows the structure of5-chloro-N-(3,5-dichlorophenyl)-2-hydroxybenzamide (Compound 3).

FIG. 8 depicts reduction in intracranial pressure (ICP) in the mousewater toxicity model withN-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide(Compound 1) at 0.76 mg/kg.

FIG. 9 depicts plasma and serum levels ofN-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide(Compound 1) converted from2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl phosphatebis ethanolamine salt.

FIG. 10 depicts mouse middle cerebral artery occlusion (MCAo) model ofischemic stroke.

FIG. 11 depicts relative change in hemispheric brain volume in the mousemiddle cerebral artery occlusion (MCAo) model.

FIG. 12 depicts neurological outcome following MCAo in mice treated withsaline (no drug, ●) or Compound 5 (o)(2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl phosphatedisodium salt).

DETAILED DESCRIPTION

The following description of the preferred embodiments is merelyexemplary in nature and is in no way intended to limit the presentdisclosure, its application, or uses.

Expression of Aquaporin-4 (AQP4) is upregulated in animal models oftrauma, stroke and water intoxication as well as around human malignantbrain tumors. Aquaporin-4 (AQP4) has been shown to play a critical rolein the development of cerebral and spinal cord edema. AQP4 provides theprimary route for water movement across the blood-brain barrier (BBB)and glia limitans. AQP4 knockout mice, without the APQ4 gene, haveimproved survival compared to wild-type mice in models of ischemicstroke, water toxicity, bacterial meningitis, and spinal cordcompression.

Cerebral edema (CE) may be generally divided into 2 major categories:vasogenic and cytotoxic. Vasogenic cerebral edema may occur when abreach in the BBB allows water and solutes to diffuse into the brain. Ithas been reported that AQP4-null mice have increased brain edema in amodel of subarachnoid hemorrhage, suggesting that AQP4 may be requiredfor the clearance of water collected in intercellular space. Incontrast, cytotoxic cerebral edema may be initiated by ischemia whichmay result in reduced plasma osmolality rather than a disrupted BBB.Ischemia may lead to a drop in ATP levels, which is thought to slow theNa—K ATPase pump resulting in an uptake of Na⁺ and Cl⁻ through leakagepathways. The net effect may be a cellular osmotic imbalance, drawingH₂O into cells—astrocytes more so than neurons—and leading to increasedICP. Mouse models for ischemic stroke, water toxicity, bacterialmeningitis, and spinal-cord compression fall into this category. Inthese models, AQP4-null mice have been reported to have reduced CEpointing to AQP4 as the central pathway for water movement into thebrain during the formation of cytotoxic CE. However, cytotoxic andvasogenic edema are not sharply divided categories; an injury thatinitially causes cytotoxic edema may be followed later, e.g., within thenext hours to days, by vasogenic edema. This may suggest differenttreatments for cerebral edema at different times.

AQP4 inhibitors may be of further utility for certain ailments wherecontrol of AQP4-medited water movement may augment neuroexcitation (byalteration of neuronal potassium homeostasis) and prove beneficial byreducing neuronal excitation, for example ailments such as fibromyalgia,multiple sclerosis, migraines and seizures (in particular but notlimited to seizures associated with epilepsy).

Glioblastoma is a common and aggressive malignant primary brain tumor.Inhibition of AQP4 in U87 human gliobastoma cell lines inducesapoptosis.

Aquaporin-2 (AQP2) is the primary route of water movement at thecollecting duct in the kidney. Blocking this water channel would lowerwater reabsorption without incurring electrolyte imbalances orinterfering with vasopressin receptor-mediated signaling. Evidence thatan AQP2 blocker would not produce electrolyte imbalances, and instead bean effective treatment for hyponatremia, comes from patients withdiabetes insipidus who lack functional AQP2. They exhibit chronicaquaresis but—if normal hydration is maintained—do not demonstrate anyother consequence of their long-term loss of AQP2 function.

Certain aquaporin inhibitors are described in International PatentApplication No. PCT/US2013/040194, which is incorporated herein byreference in entirety.

In stroke or other severely debilitating diseases or conditions, forexample where the patient may be unconscious or unable to swallow, an IVinfusion or IV bolus may be preferred. In addition, when a patient hassuffered a stroke, or traumatic brain or spinal cord injury, rapidachievement of therapeutically effective amounts of therapeutic agentmay be important to a successful therapeutic outcome. However, atherapeutic agent with only a limited solubility in water and/orphysiological media, may make IV administration of the therapeutic agentchallenging.

Accordingly, in one embodiment, provided are novel prodrug salts ofselective aquaporin inhibitors which may have improved solubility inaqueous and/or physiological media, e.g., novel prodrug salts ofN-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide which mayhave improved solubility in aqueous and/or physiological media.

A prodrug form is a derivative of an active ingredient which converts inthe body to the active ingredient, e.g., a prodrug ofN-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide is aderivative ofN-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide whichconverts in the body toN-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide.

As used herein, “alkyl” is a saturated hydrocarbon moiety, preferablyhaving one to six carbon atoms, preferably having one to four carbonatoms, which may be linear or branched. A “C₁₋₄-alkyl” is an alkylhaving one to four carbon atoms.

As used herein “alkylene” is a saturated hydrocarbon moiety, preferablyhaving one to six carbon atoms, preferably having one to four carbonatoms, which may be linear or branched and which has two points ofattachment. A C₁₋₄-alkylene is an alkylene having from one to fourcarbon atoms. For example, C₁-alkylene is methylene (—CH₂—).

As used herein, “halogen” is F, Cl, Br, or I.

As used herein, “haloalkyl” is a saturated hydrocarbon moiety,preferably having one to six carbon atoms, preferably having one to fourcarbon atoms, which may be linear or branched, and is mono-, di-, ortri-substituted with halogen. For di- or tri-substituted haloalkyl, thehalogens may be the same (e.g., dichloromethyl) or different (e.g.,chlorofluoromethyl). A C₁₋₄-haloalkyl is a haloalkyl having from one tofour carbon atoms.

As used herein, “aryl” is a mono or polycyclic (e.g., bicyclic) aromatichydrocarbon, preferably phenyl, which may be optionally substituted,e.g., optionally substituted with one or more groups independentlyselected from C₁₋₆ alkyl (e.g., methyl), halogen (e.g., Cl or F),C₁₋₆-haloalkyl (e.g., trifluoromethyl), hydroxy, and carboxy. In someembodiments, aryl, in addition to being substituted with the groupsdisclosed herein, is further substituted with an aryl or a heteroaryl toform, e.g., biphenyl or pyridylphenyl.

As used herein, “heteroaryl” is an mono or polycyclic (e.g., bicyclic)aromatic moiety wherein one or more of the atoms making up the aromaticring is sulfur or nitrogen rather than carbon, e.g., pyridyl orthiadiazolyl, which may be optionally substituted, e.g., optionallysubstituted with one or more groups independently selected from C₁₋₆alkyl (e.g., methyl), halogen (e.g., Cl or F), C₁₋₆-haloalkyl (e.g.,trifluoromethyl), hydroxy, and carboxy.

As used herein, “hydroxy” is —OH.

As used herein, “carboxy” is —COOH.

As used herein, “patient” includes human or non-human (i.e., animal)patient. In a particular embodiment, the term encompasses both human andnonhuman. In another embodiment, the term encompasses nonhuman. Inanother embodiment, the term encompasses human.

As used herein, “therapeutically effective amount” refers to an amounteffective, when administered to a human or non-human patient, to providea therapeutic benefit such as amelioration of symptoms, slowing ofdisease progression, or prevention of disease. The specific dose ofsubstance administered to obtain a therapeutic benefit will, of course,be determined by the particular circumstances surrounding the case,including, for example, the specific substance administered, the routeof administration, the condition being treated, and the individual beingtreated.

As used herein, “fairly rapid” with respect to onset of action meansthat the time it takes after a compound is administered for a responseto be observed is 30 minutes or less, for example 20 minutes or less,for example 15 minutes or less, for example 10 minutes or less, forexample 5 minutes or less, for example 1 minute or less.

As used herein, “sodium phosphate” refers to sodium dihydrogen phosphate(NaH₂PO₄), disodium hydrogen phosphate (Na₂HPO₄), and trisodiumphosphate (Na₃PO₄).

As used herein, “potassium phosphate” refers to potassium dihydrogenphosphate (KH₂PO₄), dipotassium hydrogen phosphate (K₂HPO₄), andtripotassium phosphate (K₃PO₄).

As used here, “bolus” refers to administration of a therapeutic agent ina single injection that lasts for a relatively short period of time,e.g., about 5 minutes or less, e.g., about 3 minutes or less. A bolusmay rapidly deliver a therapeutically effective amount of thetherapeutic agent to the blood.

In one embodiment, provided is a compound of Formula I

wherein:R¹, R², R³, R⁴, and R⁵ are independently H, halogen (e.g., Cl or Br),C₁₋₄-alkyl, C₁₋₄-haloalkyl (e.g., —CF₃), or cyano;one of R⁶ and R⁷ is OH and the other is O⁻Q⁺ or both of R⁶ and R⁷ areO⁻Q⁺;each Q⁻ is independently Na⁻, K⁻, HOR⁸NH₃ ⁻, (HOR⁸)₂NH₂ ⁻, or(HOR⁸)₃NH⁻, e.g., K⁻, HOR⁸NH₃ ⁺, (HOR⁸)₂NH₂ ⁺, or (HOR⁸)₃NH⁺, e.g.,HOR⁸NH₃ ⁺, (HOR⁸)₂NH₂ ⁺, or (HOR⁸)₃NH⁺; andeach R⁸ is independently C₁₋₄-alkylene (e.g., —CH₂—CH₂—).

Further provided is a compound of Formula I as follows:

-   -   1.1 Formula I wherein R¹, R², R³, R⁴, and R⁵ are independently        H, halogen (e.g., Cl or Br), C₁₋₄-haloalkyl (e.g., —CF₃), or        cyano.    -   1.2 Formula I or 1.1 wherein R¹, R², R³, R⁴, and R⁵ are        independently H, halogen (e.g., Cl or Br), or C₁₋₄-haloalkyl        (e.g., —CF₃).    -   1.3 Formula I, 1.1, or 1.2 wherein R¹, R³, and R⁵ are        independently halogen (e.g., Cl or Br) or C₁₋₄-haloalkyl (e.g.,        —CF₃) and R² and R⁴ are H.    -   1.4 Formula I or 1.1-1.3 wherein R¹, R³, and R⁵ are        independently halogen (e.g., Cl or Br) and R² and R⁴ are H.    -   1.5 Formula I or 1.1-1.4 wherein R¹, R³, and R⁵ are Cl and R²        and R⁴ are H.    -   1.6 Formula I or 1.1-1.3 wherein R¹, R³, and R⁵ are        independently C₁₋₄-haloalkyl (e.g., —CF₃) and R² and R⁴ are H.    -   1.7 Formula 1.6 wherein R¹, R³, and R⁵ are —CF₃.    -   1.8 Formula I or 1.1-1.3 wherein R¹, R³, and R⁵ are        independently F, Cl, Br, or —CF₃ and R² and R⁴ are H.    -   1.9 Formula I or 1.1-1.3 wherein R¹ is halogen (e.g., Cl or Br),        R² and R⁴ are H, and R³ and R⁵ are independently C₁₋₄-haloalkyl        (e.g., —CF₃).    -   1.10 Formula 1.8 or 1.9 wherein R¹ is Cl or Br and R³ and R⁵ are        —CF₃.    -   1.11 Formula 1.10 wherein R¹ is Cl.    -   1.12 Formula 1.10 wherein R¹ is Br.    -   1.13 Formula I or 1.1 wherein R¹, R², R³, R⁴, and R⁵ are        independently H, halogen (e.g., Cl or Br), or cyano.    -   1.14 Formula 1.13 wherein R¹ and R² are independently halogen        (e.g., Cl or Br), R³ and R⁵ are H, and R⁴ is cyano.    -   1.15 Formula 1.14 wherein R¹ and R² are Cl.    -   1.16 Formula I or 1.1-1.15 wherein R⁶ is OH and R⁷ is O⁻Q⁺.    -   1.17 Formula I or 1.1-1.15 wherein both R⁶ and R⁷ are O⁻Q⁺.    -   1.18 Formula I or 1.1-1.17 wherein each Q⁺ is independently        HOR⁸NH₃ ⁺, (HOR⁸)₂NH₂ ⁺, or (HOR⁸)₃NH⁺.    -   1.19 Formula I or 1.1-1.17 wherein each Q+ is independently        HOR⁸NH₃ ⁺.    -   1.20 Formula I or 1.1-1.17 wherein each Q+ is independently        (HOR⁸)₂NH₂ ⁺.    -   1.21 Formula I or 1.1-1.17 wherein each Q+ is independently        (HOR⁸)₃NH⁺.    -   1.22 Formula I or 1.1-1.21 wherein each R⁸ is —CH₂—CH₂—.    -   1.23 Formula I or 1.1-1.17 wherein each Q+ is Na⁺.    -   1.24 Formula I or 1.1-1.17 wherein each Q+ is K⁺.    -   1.25 Formula I wherein R¹ is halogen (e.g., Cl or Br), R² and R⁴        are H, R³ and R⁵ are independently C₁₋₄-haloalkyl (e.g., —CF₃),        R⁶ is OH, and R⁷ is O⁻Q⁺.    -   1.26 Formula 1.25 wherein R¹ is Cl or Br and R³ and R⁵ are —CF₃.    -   1.27 Formula 1.26 wherein R¹ is Cl.    -   1.28 Formula 1.25-1.27 wherein Q⁺ is HOR⁸NH₃ ⁺.    -   1.29 Formula 1.28 wherein R⁸ is —CH₂—CH₂—.    -   1.30 Formula 1.25-1.27 wherein Q⁺ is (HOR⁸)₂NH₂ ⁺.    -   1.31 Formula 1.30 wherein R⁸ is —CH₂—CH₂—.    -   1.32 Formula 1.25-1.27 wherein Q⁺ is (HOR⁸)₃NH⁺.    -   1.33 Formula 1.32 wherein R⁸ is —CH₂—CH₂—.    -   1.34 Formula 1.25-1.27 wherein Q⁺ is K⁺.    -   1.35 Formula I wherein R¹ is halogen (e.g., Cl or Br), R² and R⁴        are H, R³ and R⁵ are independently C₁₋₄-haloalkyl (e.g., —CF₃),        and both R⁶ and R⁷ are O⁻QH⁺.    -   1.36 Formula 1.35 wherein R¹ is Cl or Br and R³ and R⁵ are —CF₃.    -   1.37 Formula 1.36 wherein R¹ is Cl.    -   1.38 Formula 1.35-1.37 wherein each Q⁺ is HOR⁸NH₃ ⁺.    -   1.39 Formula 1.38 wherein each R⁸ is —CH₂—CH₂—.    -   1.40 Formula 1.35-1.37 wherein each Q⁺ is (HOR⁸)₂NH₂ ⁺.    -   1.41 Formula 1.40 wherein each R⁸ is —CH₂—CH₂—.    -   1.42 Formula 1.35-1.37 wherein each Q⁺ is (HOR⁸)₃NH⁺.    -   1.43 Formula 1.42 wherein each R⁸ is —CH₂—CH₂—.    -   1.44 Formula 1.35-1.37 wherein each Q⁺ is K⁺.    -   1.45 Formula I wherein the compound is:

-   -   1.46 Formula I wherein the compound is:

1.47 Formula I wherein the compound is:

-   -   1.48 Formula I wherein the compound is:

-   -   1.49 Formula I wherein the compound is:

-   -   1.50 Formula I wherein the compound is

-   -   1.51 Formula I wherein the compound is

-   -   1.52 Formula I wherein the compound is

In another embodiment, provided is a compound of Formula I which is acompound of Formula II

wherein:one of R⁶ and R⁷ is OH and the other is O⁻Q⁺ or both of R⁶ and R⁷ areO⁻Q⁺;each Q is independently K⁺, HOR⁸NH₃ ⁺, (HOR⁸)₂NH₂ ⁺, or (HOR⁸)₃NH⁺,e.g., HOR⁸NH₃ ⁺, (HOR⁸)₂NH₂ ⁺, or (HOR⁸)₃NH⁺; andeach R⁸ is independently C₁₋₄-alkylene (e.g., —CH₂—CH₂—).

Further provided is a compound of Formula Ia as follows:

-   -   2.1 Formula II wherein R⁶ is OH and R⁷ is O⁻Q⁺.    -   2.2 Formula II or 2.1 wherein Q⁺ is HOR⁸NH₃ ⁺, (HOR⁸)₂NH₂ ⁺, or        (HOR⁸)₃NH⁺.    -   2.3 Formula II, 2.1, or 2.2 wherein Q⁺ is HOR⁸NH₃ ⁺.    -   2.4 Formula 2.3 wherein R⁸ is —CH₂—CH₂—.    -   2.5 Formula II, 2.1, or 2.2 wherein Q⁺ is (HOR⁸)₂NH₂ ⁺.    -   2.6 Formula 2.5 wherein each R⁸ is —CH₂—CH₂—.    -   2.7 Formula II, 2.1, or 2.2 wherein Q⁺ is (HOR⁸)₃NH⁺.    -   2.8 Formula 2.7 wherein each R⁸ is —CH₂—CH₂—.    -   2.9 Formula II or 2.1 wherein Q⁺ is K⁺.    -   2.10 Formula II wherein both R⁶ and R⁷ are O⁻Q⁺.    -   2.11 Formula II or 2.10 wherein each Q⁺ is independently HOR⁸NH₃        ⁺, (HOR⁸)₂NH₂ ⁺, or (HOR⁸)₃NH⁺.    -   2.12 Formula II, 2.10, or 2.11 wherein each Q⁺ is independently        HOR⁸NH₃ ⁺.    -   2.13 Formula 2.12 wherein each R⁸ is —CH₂—CH₂—.    -   2.14 Formula II, 2.10, or 2.11 wherein each Q⁺ is independently        (HOR⁸)₂NH₂ ⁺.    -   2.15 Formula 2.14 wherein each R⁸ is —CH₂—CH₂—.    -   2.16 Formula II, 2.10, or 2.11 wherein each Q⁺ is independently        (HOR⁸)₃NH⁺.    -   2.17 Formula 2.16 wherein each R⁸ is —CH₂—CH₂—.    -   2.18 Formula II or 2.10 wherein each Q⁺ is K⁺.    -   2.19 Formula II wherein the compound is:

-   -   2.20 Formula II wherein the compound is:

-   -   2.21 Formula II wherein the compound is:

-   -   2.22 Formula II wherein the compound is:

-   -   2.23 Formula II wherein the compound is:

-   -   2.24 Formula II wherein the compound is

-   -   2.25 Formula II wherein the compound is

-   -   2.26 Formula II wherein the compound is

In yet another embodiment, provided is a pharmaceutical compositioncomprising a compound of Formula I, e.g., a compound of 1.1-1.52, and apharmaceutically acceptable excipient.

In yet another embodiment, provided is a pharmaceutical compositioncomprising a compound of Formula II, e.g., a compound of 2.1-2.26, and apharmaceutically acceptable excipient.

In yet another embodiment, provided is a method (Method A) of treatingor controlling a disease or condition mediated by an aquaporincomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of Formula I, e.g., a compound of1.1-1.52, or, e.g., a compound of Formula ITT, e.g., a compound of2.1-2.26.

Further provided is Method A as follows:

-   -   A.1 Method A wherein the aquaporin is AQP4.    -   A.2 Method A or A.1 wherein the condition to be treated or        controlled is edema, e.g. edema of the brain or spinal cord,        e.g., cerebral edema, e.g. cerebral edema consequent to head        trauma, ischemic stroke, glioma, meningitis, acute mountain        sickness, epileptic seizure, infection, metabolic disorder,        water intoxication, hepatic failure, hepatic encephalopathy, or        diabetic ketoacidosis or, e.g., spinal cord edema, e.g., spinal        cord edema consequent to spinal cord trauma, e.g., spinal cord        compression.    -   A.3 Method A, A.1, or A.2 further comprising a treatment        selected from one or more of the following: optimal head and        neck positioning to facilitate venous outflow, e.g. head        elevation 30°; avoidance of dehydration; systemic hypotension;        maintenance of normothermia or hypothermia; aggressive measures;        osmotherapy, e.g., using mannitol or hypertonic saline;        hyperventilation; therapeutic pressor therapy to enhance        cerebral perfusion; administration of barbiturates to reduce        cerebral metabolism (CMO₂); hemicraniectomy; administration of        aspirin; administration of amantadine; intravenous thrombolysis        (e.g. using rtPA); mechanical clot removal; angioplasty; and/or        stents.    -   A.4 Method A.2 wherein the patient is at elevated risk of        cerebral edema, e.g., due to head trauma, ischemic stroke,        glioma, meningitis, acute mountain sickness, epileptic seizure,        infection, metabolic disorder, water intoxication, hepatic        failure, hepatic encephalopathy, or diabetic ketoacidosis.    -   A.5 Method A.2 wherein the patient has suffered a stroke, head        injury, or spinal injury.    -   A.6 Method A.5 wherein the patient has suffered a stroke, head        injury or spinal injury within 12 hours, e.g. within 6 hours,        preferably within 3 hours of commencing treatment.    -   A.7 Method A.2 wherein the patient is at elevated risk of        suffering a stroke, head injury or spinal injury, e.g., in        combat or in an athletic competition.    -   A.8 Method A or A.1-A.7 wherein the patient already has cerebral        edema.    -   A.9 Method A or A.1-A.8 wherein the condition to be treated or        controlled is cerebral edema consequent to a stroke or a        traumatic brain injury.    -   A.10 Method A or A.1-A.9 wherein the condition to be treated or        controlled is cerebral edema consequent to a middle cerebral        artery stroke.    -   A.11 Method A or A.1-A.9 wherein the condition to be treated or        controlled is cerebral edema consequent to closed head trauma.    -   A.12 Method A or A.1-A.4 wherein the condition to be treated or        controlled is cerebral edema consequent to an epileptic seizure.    -   A.13 Method A or A.1-A.4 wherein the condition to be treated or        controlled is cerebral edema consequent to an infection.    -   A.14 Method A or A.1-A.4 wherein the condition to be treated or        controlled is cerebral edema consequent to a metabolic disorder.    -   A.15 Method A or A.1-A.4 wherein the condition to be treated or        controlled is cerebral edema consequent to glioma.    -   A.16 Method A or A.1-A.4 wherein the condition to be treated or        controlled is cerebral edema consequent to meningitis.    -   A.17 Method A or A.1-A.4 wherein the condition to be treated or        controlled is cerebral edema consequent to acute mountain        sickness.    -   A.18 Method A or A.1-A.4 wherein the condition to be treated or        controlled is cerebral edema consequent to water intoxication.    -   A.19 Method A or A.1-A.4 wherein the condition to be treated or        controlled is cerebral edema consequent to hepatic failure,        hepatic encephalopathy, or diabetic ketoacidosis.    -   A.20 Method A or A.1-A.3 wherein the condition to be treated or        controlled is cerebral edema consequent to an abscess.    -   A.21 Method A or A.1-A.3 wherein the condition to be treated or        controlled is cerebral edema consequent to eclampsia.    -   A.22 Method A or A.1-A.3 wherein the condition to be treated or        controlled is cerebral edema consequent to Creutzfeldt-Jakob        disease.    -   A.23 Method A or A.1-A.3 wherein the condition to be treated or        controlled is cerebral edema consequent to lupus cerebritis.    -   A.24 Method A or A.1-A.3 wherein the condition to be treated or        controlled is edema consequent to hypoxia, e.g., general        systemic hypoxia, e.g., hypoxia caused by an interruption of        blood perfusion, for example wherein the edema is cerebral edema        consequent to hypoxia caused by cardiac arrest, stroke, or other        interruption of blood perfusion to the brain, or wherein the        edema is cardiac edema consequent to cardiac ischemia or other        interruption of blood flow to the heart.    -   A.25 Method A or A.1-A.3 wherein the condition to be treated or        controlled is cerebral edema consequent to microgravity and/or        radiation exposure, e.g., exposure from space flight or from        working with radioactive materials or from working in        radioactive areas.    -   A.26 Method A or A.1-A.3 wherein the condition to be treated or        controlled is cerebral edema consequent to an invasive central        nervous system procedure, e.g., neurosurgery, endovascular clot        removal, spinal tap, aneurysm repair, or deep brain stimulation.    -   A.27 Method A.25 or A.26 wherein the patient is at elevated risk        of edema, e.g., due to microgravity and/or radiation exposure,        neurosurgery, endovascular clot removal, spinal tap, aneurysm        repair, or deep brain stimulation.    -   A.28 Method A.25 or A.26 wherein the patient already has edema.    -   A.29 Method A or A.1-A.28 wherein the edema is cytotoxic        cerebral edema or is primarily cytotoxic cerebral edema.    -   A.30 Method A, A.1-A.19, or A.24 wherein the edema is cytotoxic        cerebral edema or is primarily cytotoxic cerebral edema.    -   A.31 Method A, A.1, or A.2 wherein the condition to be treated        or controlled is spinal cord edema, e.g., spinal cord edema        consequent to a spinal cord trauma, e.g., spinal cord        compression.    -   A.32 Method A.31 wherein the condition to be treated or        controlled is spinal cord edema consequent to spinal cord        compression.    -   A.33 Method A, A.1, or A.2 wherein the condition to be treated        or controlled is optic nerve edema, e.g., optic nerve edema        consequent to microgravity and/or radiation exposure, e.g.,        exposure from space flight or from working with radioactive        materials or from working in radioactive areas.    -   A.34 Method A, A.1, or A.2 wherein the condition to be treated        or controlled is retinal edema.    -   A.35 Method A, A.1, or A.2 wherein the condition to be treated        or controlled is pulmonary edema.    -   A.36 Method A or A.1 wherein the condition to be treated or        controlled is epilepsy.    -   A.37 Method A or A.1 wherein the condition to be treated or        controlled is retinal ischemia or other diseases of the eye        associated with abnormalities in intraocular pressure and/or        tissue hydration.    -   A.38 Method A or A.1 wherein the condition to be treated or        controlled is myocardial ischemia.    -   A.39 Method A or A.1, wherein the condition to be treated or        controlled is myocardial ischemia/reperfusion injury.    -   A.40 Method A or A.1 wherein the condition to be treated or        controlled is myocardial infarction.    -   A.41 Method A or A.1 wherein the condition to be treated or        controlled is myocardial hypoxia.    -   A.42 Method A or A.1 wherein the condition to be treated or        controlled is congestive heart failure.    -   A.43 Method A or A.1 wherein the condition to be treated or        controlled is sepsis.    -   A.44 Method A or A.1 wherein the condition to be treated or        controlled is a migraine.    -   A.45 Method A or A.1 wherein the condition to be treated or        controlled is neuromyelitis optica.    -   A.46 Method A or A.1 wherein the condition to be treated or        controlled is glioblastoma.    -   A.47 Method A or A.1 wherein the condition to be treated or        controlled is fibromyalgia.    -   A.48 Method A or A.1 wherein the condition to be treated or        controlled is multiple sclerosis.    -   A.49 Method A wherein the aquaporin is AQP2.    -   A.50 Method A or A.49 wherein the condition to be treated or        controlled is hyponatremia or excessive fluid retention, e.g.,        consequent to heart failure (HF), for example congestive heart        failure, liver cirrhosis, nephrotic disorder, syndrome of        inappropriate antidiuretic hormone secretion (SIADH), or        infertility treatment.    -   A.51 Method A, A.49, or A.50 wherein the condition to be treated        or controlled is ovarian hyperstimulation syndrome.    -   A.52 Method A, A.49, or A.51 further comprising one or more of        restriction of dietary sodium, fluid and/or alcohol; and/or        administration of one or more diuretics, vasopressin receptor        antagonists, angiotensin converting enzyme (ACE) inhibitors,        aldosterone inhibitors, angiotensin receptor blockers (ARBs),        beta-adrenergic antagonists (beta-blockers), and/or digoxin.    -   A.53 Method A or A.1-A.52 wherein the compound of Formula I,        e.g., the compound of 1.1-1.52, or, e.g., the compound of        Formula II, e.g., the compound of 2.1-2.26, is administered        orally.    -   A.54 Method A or A.1-A.52 wherein the compound of Formula I,        e.g., the compound of 1.1-1.52, or, e.g., the compound of        Formula II, e.g., the compound of 2.1-2.26, is administered        parenterally.    -   A.55 Method A.54 wherein the compound of Formula I, e.g., the        compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, is administered by injection,        e.g., subcutaneously, intramuscularly, intravenously, or        intrathecally, e.g., a bolus injected subcutaneously,        intramuscularly, intravenously, or intrathecally.    -   A.56 Method A.55 wherein the compound of Formula I, e.g., the        compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, is administered intravenously,        e.g., IV bolus and/or IV infusion, e.g., IV bolus followed by IV        infusion.    -   A.57 Method A or A.1-A.56 wherein the patient is human.    -   A.58 Method A or A.1-A.57 wherein the onset of action after        administration of the compound of Formula I, e.g., the compound        of 1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, is fairly rapid.

In yet another embodiment, provided is a method (Method B) of treatingor controlling edema, e.g. edema of the brain or spinal cord, e.g.,cerebral edema, e.g. cerebral edema consequent to head trauma, ischemicstroke, glioma, meningitis, acute mountain sickness, epileptic seizure,infection, metabolic disorder, hypoxia, water intoxication, hepaticfailure, hepatic encephalopathy, diabetic ketoacidosis, abscess,eclampsia, Creutzfeldt-Jakob disease, lupus cerebritis, cardiac arrest,microgravity and/or radiation exposure, or invasive central nervoussystem procedures, e.g., neurosurgery, endovascular clot removal, spinaltap, aneurysm repair, or deep brain stimulation or, e.g., optic nerveedema, e.g., optic nerve edema consequent to microgravity and/orradiation exposure or, e.g., retinal edema or, e.g., spinal cord edema,e.g., spinal cord edema consequent to spinal cord trauma, e.g., spinalcord compression, or, e.g., pulmonary edema, comprising administering atherapeutically effective amount of a prodrug salt of an inhibitor ofAQP4, e.g., a compound of Formula I, e.g., a compound of 1.1-1.52, or,e.g., a compound of Formula II, e.g., a compound of 2.1-2.26, to apatient in need thereof.

Further provided is Method B as follows:

-   -   B.1 Method B further comprising a treatment selected from one or        more of the following: optimal head and neck positioning to        facilitate venous outflow, e.g. head elevation 30°; avoidance of        dehydration; systemic hypotension; maintenance of normothermia        or hypothermia; aggressive measures; osmotherapy, e.g., using        mannitol or hypertonic saline; hyperventilation; therapeutic        pressor therapy to enhance cerebral perfusion; administration of        barbiturates to reduce cerebral metabolism (CMO₂);        hemicraniectomy; administration of aspirin; administration of        amantadine; intravenous thrombolysis (e.g. using rtPA);        mechanical clot removal; angioplasty; and/or stents.    -   B.2 Method B wherein the patient is at elevated risk of cerebral        edema, e.g., due to head trauma, ischemic stroke, glioma,        meningitis, acute mountain sickness, epileptic seizure,        infection, metabolic disorder, water intoxication, hepatic        failure, hepatic encephalopathy, or diabetic ketoacidosis.    -   B.3 Method B wherein the patient has suffered a stroke, head        injury, or spinal injury.    -   B.4 Method B.3 wherein the patient has suffered a stroke, head        injury or spinal injury within 12 hours, e.g. within 6 hours,        preferably within 3 hours of commencing treatment.    -   B.5 Method B wherein the patient is at elevated risk of        suffering a stroke, head injury or spinal injury, e.g., in        combat or in an athletic competition.    -   B.6 Method B or B.1-B.5 wherein the patient already has cerebral        edema.    -   B.7 Method B or B.1-B.6 wherein the condition to be treated or        controlled is cerebral edema consequent to a stroke or a        traumatic brain injury.    -   B.8 Method B or B.1-B.7 wherein the condition to be treated or        controlled is cerebral edema consequent to a middle cerebral        artery stroke.    -   B.9 Method B or B.1-B.7 wherein the condition to be treated or        controlled is cerebral edema consequent to a closed head trauma.    -   B.10 Method B, B.1, or B.2 wherein the condition to be treated        or controlled is cerebral edema consequent to an epileptic        seizure.    -   B.11 Method B, B.1, or B.2 wherein the condition to be treated        or controlled is cerebral edema consequent to an infection.    -   B.12 Method B, B.1, or B.2 wherein the condition to be treated        or controlled is cerebral edema consequent to a metabolic        disorder.    -   B.13 Method B, B.1, or B.2 wherein the condition to be treated        or controlled is cerebral edema consequent to glioma.    -   B.14 Method B, B.1, or B.2 wherein the condition to be treated        or controlled is cerebral edema consequent to meningitis.    -   B.15 Method B, B.1, or B.2 wherein the condition to be treated        or controlled is cerebral edema consequent to acute mountain        sickness.    -   B.16 Method B, B.1, or B.2 wherein the condition to be treated        or controlled is cerebral edema consequent to water        intoxication.    -   B.17 Method B, B.1, or B.2 wherein the condition to be treated        or controlled is cerebral edema consequent to hepatic failure,        hepatic encephalopathy, or diabetic ketoacidosis.    -   B.18 Method B or B. 1 wherein the condition to be treated or        controlled is cerebral edema consequent to an abscess.    -   B.19 Method B or B. 1 wherein the condition to be treated or        controlled is cerebral edema consequent to eclampsia.    -   B.20 Method B or B. 1 wherein the condition to be treated or        controlled is cerebral edema consequent to Creutzfeldt-Jakob        disease.    -   B.21 Method B or B.1 wherein the condition to be treated or        controlled is cerebral edema consequent to lupus cerebritis.    -   B.22 Method B or B.1 wherein the condition to be treated or        controlled is edema consequent to hypoxia, e.g., general        systemic hypoxia, e.g., hypoxia caused by an interruption of        blood perfusion, for example wherein the edema is cerebral edema        consequent to hypoxia caused by cardiac arrest, stroke, or other        interruption of blood perfusion to the brain, or wherein the        edema is cardiac edema consequent to cardiac ischemia or other        interruption of blood flow to the heart.    -   B.23 Method B or B. 1 wherein the condition to be treated or        controlled is cerebral consequent to microgravity exposure,        e.g., exposure from space flight or from working with        radioactive materials or from working in radioactive areas.    -   B.24 Method B or B.1 wherein the condition to be treated or        controlled is cerebral edema consequent to invasive central        nervous system procedures, e.g., neurosurgery, endovascular clot        removal, spinal tap, aneurysm repair, or deep brain stimulation.    -   B.25 Method B.23 or B.24 wherein the patient is at elevated risk        of edema, e.g., due to microgravity and/or radiation exposure,        neurosurgery, endovascular clot removal, spinal tap, aneurysm        repair, or deep brain stimulation.    -   B.26 Method B.23 or B.24 wherein the patient already has edema.    -   B.27 Method B or B.1-B.26 wherein the edema is cytotoxic        cerebral edema or is primarily cytotoxic cerebral edema.    -   B.28 Method B, B.1-B. 17, or B.22 wherein the edema is cytotoxic        cerebral edema or is primarily cytotoxic cerebral edema.    -   B.29 Method B wherein the condition to be treated or controlled        is spinal cord edema, e.g., spinal cord edema consequent to        spinal cord trauma, e.g., spinal cord compression.    -   B.30 Method B.29 wherein the condition to be treated or        controlled is spinal cord edema consequent to spinal cord        compression.    -   B.31 Method B wherein the condition to be treated or controlled        is optic nerve edema, e.g., optic nerve edema consequent to        microgravity and/or radiation exposure, e.g., exposure from        space flight or from working with radioactive materials or from        working in radioactive areas.    -   B.32 Method B wherein the condition to be treated or controlled        is retinal edema.    -   B.33 Method B wherein the condition to be treated or controlled        is pulmonary edema.    -   B.34 Method B or B. 1-B.33 wherein the duration of treatment        with the prodrug salt of an AQP4 inhibitor, e.g., a compound of        Formula I, e.g., a compound of 1.1-1.52, or, e.g., a compound of        Formula II, e.g., a compound of 2.1-2.26, is less than 21 days,        e.g., less than 2 weeks, e.g., one week or less.    -   B.35 Method B or B. 1-B.34 wherein the prodrug salt of an AQP4        inhibitor, e.g., the compound of Formula I, e.g., the compound        of 1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, is administered orally.    -   B.36 Method B or B.1-B.34 wherein the prodrug salt of an AQP4        inhibitor, e.g., the compound of Formula I, e.g., the compound        of 1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, is administered parenterally.    -   B.37 Method B.36 wherein the prodrug salt of an AQP4 inhibitor,        e.g., the compound of Formula I, e.g., the compound of 1.1-1.52,        or, e.g., the compound of Formula II, e.g., the compound of        2.1-2.26, is administered by injection, e.g., subcutaneously,        intramuscularly, intravenously, or intrathecally, e.g., a bolus        administered subcutaneously, intramuscularly, intravenously, or        intrathecally.    -   B.38 Method B.37 wherein the prodrug salt of an AQP4 inhibitor,        e.g., the compound of Formula I, e.g., the compound of 1.1-1.52,        or, e.g., the compound of Formula II, e.g., the compound of        2.1-2.26, is administered intravenously, e.g., IV bolus and/or        IV infusion, e.g., IV bolus followed by IV infusion.    -   B.39 Method B or B.1-B.38 wherein the patient is human.    -   B.40 Method B or B. 1-B.39 wherein the onset of action after        administration of the prodrug salt of an AQP4 inhibitor, e.g.,        the compound of Formula I, e.g., the compound of 1.1-1.52, or,        e.g., the compound of Formula II, e.g., the compound of        2.1-2.26, is fairly rapid.    -   B.41 Method B or B.1-B.40 wherein the AQP4 inhibitor binds to        AQP4.

In yet another embodiment, provided is a method (Method C) of treatingor controlling a condition selected from hyponatremia and excessivefluid retention, e.g., consequent to heart failure (HF), for examplecongestive heart failure, liver cirrhosis, nephrotic disorder, syndromeof inappropriate antidiuretic hormone secretion (SIADH), or infertilitytreatment, comprising administering a therapeutically effective amountof a prodrug salt of an inhibitor of AQP2, e.g., a compound of FormulaI, e.g., a compound of 1.1-1.52, or, e.g., a compound of Formula II,e.g., a compound of 2.1-2.26, to a patient in need thereof.

Further provided is Method C as follows:

-   -   C.1 Method C further comprising one or more of restriction of        dietary sodium, fluid and/or alcohol; and/or administration of        one or more diuretics, vasopressin receptor antagonists,        angiotensin converting enzyme (ACE) inhibitors, aldosterone        inhibitors, angiotensin receptor blockers (ARBs),        beta-adrenergic antagonists (beta-blockers), and/or digoxin.    -   C.2 Method C or C.1 wherein the prodrug salt of an AQP2        inhibitor, the compound of Formula I, e.g., the compound of        1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, is administered orally.    -   C.3 Method C or C.1 wherein the prodrug salt of an AQP2        inhibitor, e.g., the compound of Formula I, e.g., the compound        of 1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, is administered parenterally.    -   C.4 Method C.3 wherein the prodrug salt of an AQP2 inhibitor,        e.g., the compound of Formula I, e.g., the compound of 1.1-1.52,        or, e.g., the compound of Formula II, e.g., the compound of        2.1-2.26, is administered by injection, e.g., subcutaneously,        intramuscularly, intravenously, or intrathecally, e.g., a bolus        injected subcutaneously, intramuscularly, intravenously, or        intrathecally.    -   C.5 Method C.4 wherein the prodrug salt of an AQP2 inhibitor,        e.g., the compound of Formula I, e.g., the compound of 1.1-1.52,        or, e.g., the compound of Formula II, e.g., the compound of        2.1-2.26, is administered intravenously, e.g., IV bolus and/or        IV infusion, e.g., IV bolus followed by IV infusion.    -   C.6 Method C or C.1-C.5 wherein the patient is human.    -   C.7 Method C or C.1-C.6 wherein the onset of action after        administration of the prodrug salt of an AQP2 inhibitor, e.g.,        the compound of Formula I, e.g., the compound of 1.1-1.52, or,        e.g., the compound of Formula II, e.g., the compound of        2.1-2.26, is fairly rapid.    -   C.8 Method C or C.1-C.7 wherein the AQP2 inhibitor binds to        AQP2.

In yet another embodiment, provided is a method (Method D) of treatingor controlling a condition selected from epilepsy, retinal ischemia orother diseases of the eye associated with abnormalities in intraocularpressure and/or tissue hydration, myocardial ischemia, myocardialischemia/reperfusion injury, myocardial infarction, myocardial hypoxia,congestive heart failure, sepsis, neuromyelitis optica, glioblastoma,fibromyalgia, multiple sclerosis, and a migraine comprisingadministering a therapeutically effective amount of a prodrug salt of aninhibitor of AQP4, e.g., a compound of Formula 1, e.g., a compound of1.1-1.52, or, e.g., a compound of Formula II, e.g., the compound of2.1-2.26, to a patient in need thereof.

Further provided is Method D as follows:

-   -   D.1 Method D wherein the condition to be treated or controlled        is retinal ischemia or other diseases of the eye associated with        abnormalities in intraocular pressure and/or tissue hydration.    -   D.2 Method D wherein the condition to be treated or controlled        is myocardial ischemia.    -   D.3 Method D wherein the condition to be treated or controlled        is myocardial ischemia/reperfusion injury.    -   D.4 Method D wherein the condition to be treated or controlled        is myocardial infarction.    -   D.5 Method D wherein the condition to be treated or controlled        is myocardial hypoxia.    -   D.6 Method D wherein the condition to be treated or controlled        is congestive heart failure.    -   D.7 Method D wherein the condition to be treated or controlled        is sepsis.    -   D.8 Method D wherein the condition to be treated or controlled        is neuromyelitis optica.    -   D.9 Method D wherein the condition to be treated or controlled        is glioblastoma.    -   D.10 Method D wherein the condition to be treated or controlled        is fibromyalgia.    -   D.11 Method D wherein the condition to be treated or controlled        is multiple sclerosis.    -   D.12 Method D wherein the condition to be treated or controlled        is a migraine.    -   D.13 Method D or D.1-D. 12 wherein the prodrug salt of an AQP4        inhibitor, e.g., the compound of Formula I, e.g., the compound        of 1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, is administered orally.    -   D.14 Method D or D.1-D.12 wherein the prodrug salt of an AQP4        inhibitor, e.g., the compound of Formula I, e.g., the compound        of 1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, is administered parenterally.    -   D.15 Method D. 14 wherein the prodrug salt of an AQP4 inhibitor,        e.g., the compound of Formula I, e.g., the compound of 1.1-1.52,        or, e.g., the compound of Formula II, e.g., the compound of        2.1-2.26, is administered by injection, e.g., subcutaneously,        intramuscularly, intravenously, or intrathecally, e.g., a bolus        injected subcutaneously, intramuscularly, intravenously, or        intrathecally.    -   D.16 Method D.15 wherein the prodrug salt of an AQP4 inhibitor,        e.g., the compound of Formula I, e.g., the compound of 1.1-1.52,        or, e.g., the compound of Formula II, e.g., the compound of        2.1-2.26, is administered intravenously, e.g., IV bolus and/or        IV infusion, e.g., IV bolus followed by IV infusion.    -   D.17 Method D or D.1-D.16 wherein the patient is human.    -   D.18 Method D or D.1-D.17 wherein the onset of action after        administration of the prodrug salt of an AQP4 inhibitor, e.g.,        the compound of Formula 1, e.g., the compound of 1.1-1.52, or,        e.g., the compound of Formula II, e.g., the compound of        2.1-2.26, is fairly rapid.    -   D.19 Method D or D.1-D.18 wherein the AQP4 inhibitor binds to        AQP4.

In yet another embodiment, provided is a method (Method E) of treatingor controlling a disease or condition mediated by an aquaporincomprising administering to a patient in need thereof a prodrug salt ofthe aquaporin inhibitor, e.g., a compound of Formula I, e.g., a compoundof 1.1-1.52, or, e.g., a compound of Formula II, e.g., a compound of2.1-2.26, in an amount effective to inhibit the aquaporin.

Further provided is Method E as follows:

-   -   E.1 Method E wherein the aquaporin is AQP4.    -   E.2 Method E or E.1 wherein the condition to be treated or        controlled is selected from edema, e.g. edema of the brain or        spinal cord, e.g., cerebral edema, e.g. cerebral edema        consequent to head trauma, ischemic stroke, glioma, meningitis,        acute mountain sickness, epileptic seizure, infection, metabolic        disorder, water intoxication, hepatic failure, hepatic        encephalopathy, or diabetic ketoacidosis or, e.g., spinal cord        edema, e.g., spinal cord edema consequent to spinal cord trauma,        e.g., spinal cord compression.    -   E.3 Method E, E. 1, or E.2 further comprising a treatment        selected from one or more of the following: optimal head and        neck positioning to facilitate venous outflow, e.g. head        elevation 300; avoidance of dehydration; systemic hypotension;        maintenance of normothermia or hypothermia; aggressive measures;        osmotherapy, e.g., using mannitol or hypertonic saline;        hyperventilation; therapeutic pressor therapy to enhance        cerebral perfusion; administration of barbiturates to reduce of        cerebral metabolism (CMO₂); hemicraniectomy; administration of        aspirin; administration of amantadine; intravenous thrombolysis        (e.g. using rtPA); mechanical clot removal; angioplasty; and/or        stents.    -   E.4 Method E.2 wherein the patient is at elevated risk of        cerebral edema, e.g., due to head trauma, ischemic stroke,        glioma, meningitis, acute mountain sickness, epileptic seizure,        infection, metabolic disorder, water intoxication, hepatic        failure, hepatic encephalopathy, or diabetic ketoacidosis.    -   E.5 Method E.2 wherein the patient has suffered a stroke, head        injury, or spinal injury.    -   E.6 Method E.5 wherein the patient has suffered a stroke, head        injury or spinal injury within 12 hours, e.g. within 6 hours,        preferably within 3 hours of commencing treatment.    -   E.7 Method E.2 wherein the patient is at elevated risk of        suffering a stroke, head injury or spinal injury, e.g., in        combat or in an athletic competition.    -   E.8 Method E or E.1-E.7 wherein the patient already has cerebral        edema.    -   E.9 Method E or E.1-E.8 wherein the condition to be treated or        controlled is cerebral edema consequent to a stroke or a        traumatic brain injury.    -   E.10 Method E or E.1-E.9 wherein the condition to be treated or        controlled is cerebral edema consequent to a middle cerebral        artery stroke.    -   E.11 Method E or E.1-E.9 wherein the condition to be treated or        controlled is cerebral edema consequent to a closed head trauma.    -   E.12 Method E or E.1-E.4 wherein the condition to be treated or        controlled is cerebral edema consequent to an epileptic seizure.    -   E.13 Method E or E.1-E.4 wherein the condition to be treated or        controlled is cerebral edema consequent an infection.    -   E.14 Method E or E.1-E.4 wherein the condition to be treated or        controlled is cerebral edema consequent to a metabolic disorder.    -   E.15 Method E or E.1-E.4 wherein the condition to be treated or        controlled is cerebral edema consequent to glioma.    -   E.16 Method E or E.1-E.4 wherein the condition to be treated or        controlled is cerebral edema consequent to meningitis.    -   E.17 Method E or E.1-E.4 wherein the condition to be treated or        controlled is cerebral edema consequent to acute mountain        sickness.    -   E.18 Method E or E.1-E.4 wherein the condition to be treated or        controlled is cerebral edema consequent to water intoxication.    -   E.19 Method E or E.1-E.4 wherein the condition to be treated or        controlled is cerebral edema consequent to hepatic failure,        hepatic encephalopathy, or diabetic ketoacidosis.    -   E.20 Method E or E.1-E.3 wherein the condition to be treated or        controlled is cerebral edema consequent to an abscess.    -   E.21 Method E or E.1-E.3 wherein the condition to be treated or        controlled is cerebral edema consequent to eclampsia.    -   E.22 Method E or E.1-E.3 wherein the condition to be treated or        controlled is cerebral edema consequent to Creutzfeldt-Jakob        disease.    -   E.23 Method E or E.1-E.3 wherein the condition to be treated or        controlled is cerebral edema consequent to lupus cerebritis.    -   E.24 Method E or E.1-E.3 wherein the condition to be treated or        controlled is edema consequent to hypoxia, e.g., general        systemic hypoxia, e.g., hypoxia caused by an interruption of        blood perfusion, for example wherein the edema is cerebral edema        consequent to hypoxia caused by cardiac arrest, stroke, or other        interruption of blood perfusion to the brain, or wherein the        edema is cardiac edema consequent to cardiac ischemia or other        interruption of blood flow to the heart.    -   E.25 Method E or E.1-E.3 wherein the condition to be treated or        controlled is cerebral edema consequent to microgravity and/or        radiation exposure, e.g., exposure from space flight or from        working with radioactive materials or from working in        radioactive areas.    -   E.26 Method E or E.1-E.3 wherein the condition to be treated or        controlled is cerebral edema consequent to invasive central        nervous system procedures, e.g., neurosurgery, endovascular clot        removal, spinal tap, aneurysm repair, or deep brain stimulation.    -   E.27 Method E.25 or E.26 wherein the patient is at elevated risk        of edema, e.g., due to microgravity and/or radiation exposure,        neurosurgery, endovascular clot removal, spinal tap, aneurysm        repair, or deep brain stimulation.    -   E.28 Method E.25 or E.26 wherein the patient already has edema.    -   E.29 Method E or E.1-E.28 wherein the edema is cytotoxic        cerebral edema or is primarily cytotoxic cerebral edema.    -   E.30 Method E, E.1-E.19, or E.24 wherein the edema is cytotoxic        cerebral edema or is primarily cytotoxic cerebral edema.    -   E.31 Method E, E.1, or E.2 wherein the condition to be treated        or controlled is spinal cord edema, e.g., spinal cord edema        consequent to spinal cord trauma, e.g., spinal cord compression.    -   E.32 Method E.31 wherein the condition to be treated or        controlled is spinal cord edema consequent to spinal cord        compression.    -   E.33 Method E, E.1, or E.2 wherein the condition to be treated        or controlled is optic nerve edema, e.g., optic nerve edema        consequent to microgravity and/or radiation exposure, e.g.,        exposure from space flight or from working with radioactive        materials or from working in radioactive areas.    -   E.34 Method E, E. 1, or E.2 wherein the condition to be treated        or controlled is retinal edema.    -   E.35 Method E, E.1, or E.2 wherein the condition to be treated        or controlled is pulmonary edema.    -   E.36 Method E or E.1 wherein the condition to be treated or        controlled is epilepsy.    -   E.37 Method E or E. 1 wherein the condition to be treated or        controlled is retinal ischemia or other diseases of the eye        associated with abnormalities in intraocular pressure and/or        tissue hydration.    -   E.38 Method E or E.1 wherein the condition to be treated or        controlled is myocardial ischemia.    -   E.39 Method E or E. 1 wherein the condition to be treated or        controlled is myocardial ischemia/reperfusion injury.    -   E.40 Method E or E.1 wherein the condition to be treated or        controlled is myocardial infarction.    -   E.41 Method E or E.1 wherein the condition to be treated or        controlled is myocardial hypoxia.    -   E.42 Method E or E. 1 wherein the condition to be treated or        controlled is congestive heart failure.    -   E.43 Method E or E. 1 wherein the condition to be treated or        controlled is sepsis.    -   E.44 Method E or E. 1 wherein the condition to be treated or        controlled is a migraine.    -   E.45 Method E or E.1 wherein the condition to be treated or        controlled is neuromyelitis optica.    -   E.46 Method E or E.1 wherein the condition to be treated or        controlled is glioblastoma.    -   E.47 Method E or E. 1 wherein the condition to be treated or        controlled is fibromyalgia.    -   E.48 Method E or E. 1 wherein the condition to be treated or        controlled is multiple sclerosis.    -   E.49 Method E wherein the aquaporin is AQP2.    -   E.50 Method E or E.49 wherein the condition to be treated is        hyponatremia or excessive fluid retention, e.g., consequent to        heart failure (HF), for example congestive heart failure, liver        cirrhosis, nephrotic disorder, syndrome of inappropriate        antidiuretic hormone secretion (SIADH), or infertility        treatment.    -   E.51 Method E, E.49, or E.50 wherein the condition to be treated        or controlled is ovarian hyperstimulation syndrome.    -   E.52 Method E, E.49, or E.50 further comprising one or more of        restriction of dietary sodium, fluid and/or alcohol; and/or        administration of one or more diuretics, vasopressin receptor        antagonists, angiotensin converting enzyme (ACE) inhibitors,        aldosterone inhibitors, angiotensin receptor blockers (ARBs),        beta-adrenergic antagonists (beta-blockers), and/or digoxin.    -   E.53 Method E or E.1-E.52 wherein the duration of treatment with        the prodrug salt of the aquaporin inhibitor, e.g., the compound        of Formula I, e.g., the compound of 1.1-1.52, or, e.g., the        compound of Formula II, e.g., the compound of 2.1-2.26, is less        than 21 days, e.g., less than 2 weeks, e.g., one week or less.    -   E.54 Method E or E.1-E.53 wherein the prodrug salt of the        aquaporin inhibitor, e.g., the compound of Formula 1, e.g., the        compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, is administered orally.    -   E.55 Method E or E.1-E.53 wherein the prodrug salt of the        aquaporin inhibitor, e.g., the compound of Formula I, e.g., the        compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, is administered parenterally.    -   E.56 Method E.55 wherein the prodrug salt of the aquaporin        inhibitor, e.g., the compound of Formula I, e.g., the compound        of 1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, is administered by injection, e.g.,        subcutaneously, intramuscularly, intravenously, or        intrathecally, e.g., a bolus injected subcutaneously,        intramuscularly, intravenously, or intrathecally.    -   E.57 Method E.56 wherein the prodrug salt of the aquaporin        inhibitor, e.g., the compound of Formula I, e.g., the compound        of 1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, is administered intravenously, e.g., IV        bolus and/or IV infusion, e.g., IV bolus followed by IV        infusion.    -   E.58 Method E or E.1-E.57 wherein the patient is human.    -   E.59 Method E or E.1-E.58 wherein the onset of action after        administration of the prodrug salt of the aquaporin inhibitor,        e.g., the compound of Formula I, e.g., the compound of 1.1-1.52,        or, e.g., the compound of Formula II, e.g., the compound of        2.1-2.26, is fairly rapid.

In a further embodiment, provided is a method (Method F) of inhibitingan aquaporin in vivo comprising administering a compound of Formula I,e.g., a compound of 1.1-1.52, or, e.g., a compound of Formula II, e.g.,a compound of 2.1-2.26, in an amount effective to inhibit the aquaporin.

Further provided is Method F as follows:

-   -   F.1 Method F wherein the aquaporin is AQP4.    -   F.2 Method F wherein the aquaporin is AQP2.    -   F.3 Method F, F.1, or F.2 wherein the compound of Formula T,        e.g., the compound of 1.1-1.52, or, e.g., the compound of        Formula II, e.g., the compound of 2.1-2.26, is administered        orally.    -   F.4 Method F, F.1, or F.2 wherein the compound of Formula I,        e.g., the compound of 1.1-1.52, or, e.g., the compound of        Formula II, e.g., the compound of 2.1-2.26, is administered        parenterally.    -   F.5 Method of F.4 wherein the compound of Formula I, e.g., the        compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, is administered intravenously,        e.g., IV bolus and/or IV infusion, e.g., IV bolus followed by IV        infusion.

In a further embodiment, provided is a method (Method G) to inhibit anaquaporin in a patient suffering from a disease or condition mediated byan aquaporin comprising administering an effective amount of a prodrugsalt of an inhibitor of the aquaporin, e.g., a compound of Formula I,e.g., a compound of 1.1-1.52, or, e.g., a compound of Formula II, e.g.,a compound of 2.1-2.26, to inhibit the aquaporin.

Further provided is Method G as follows:

-   -   G.1 Method G wherein the aquaporin is AQP4.    -   G.2 Method G or G.1 wherein the condition to be treated or        controlled is edema, e.g. edema of the brain or spinal cord,        e.g., cerebral edema, e.g. cerebral edema consequent to head        trauma, ischemic stroke, glioma, meningitis, acute mountain        sickness, epileptic seizure, infection, metabolic disorder,        water intoxication, hepatic failure, hepatic encephalopathy, or        diabetic ketoacidosis or, e.g., spinal cord edema, e.g., spinal        cord edema consequent to spinal cord trauma, e.g., spinal cord        compression.    -   G.3 Method G, G.1, or G.2 further comprising a treatment        selected from one or more of the following: optimal head and        neck positioning to facilitate venous outflow, e.g. head        elevation 300; avoidance of dehydration; systemic hypotension;        maintenance of normothermia or hypothermia; aggressive measures;        osmotherapy, e.g., using mannitol or hypertonic saline;        hyperventilation; therapeutic pressor therapy to enhance        cerebral perfusion; administration of barbiturates to reduce        cerebral metabolism (CMO₂); hemicraniectomy; administration of        aspirin; administration of amantadine; intravenous thrombolysis        (e.g. using rtPA); mechanical clot removal; angioplasty; and/or        stents.    -   G.4 Method G.2 wherein the patient is at elevated risk of        cerebral edema, e.g., due to head trauma, ischemic stroke,        glioma, meningitis, acute mountain sickness, epileptic seizure,        infection, metabolic disorder, water intoxication, hepatic        failure, hepatic encephalopathy, or diabetic ketoacidosis.    -   G.5 Method G.2 wherein the patient has suffered a stroke, head        injury, or spinal injury.    -   G.6 Method G.5 wherein the patient has suffered a stroke, head        injury or spinal injury within 12 hours, e.g. within 6 hours,        preferably within 3 hours of commencing treatment.    -   G.7 Method G.2 wherein the patient is at elevated risk of        suffering a stroke, head injury or spinal injury, e.g., in        combat or in an athletic competition.    -   G.8 Method G or G.1-G.7 wherein the patient already has cerebral        edema.    -   G.9 Method G or G.1-G.8 wherein the condition to be treated or        controlled is cerebral edema consequent to a stroke or a        traumatic brain injury.    -   G.10 Method G or G.1-G.9 wherein the condition to be treated or        controlled is cerebral edema consequent to a middle cerebral        artery stroke.    -   G.11 Method G or G.1-G.9 wherein the condition to be treated or        controlled is cerebral edema consequent to closed head trauma.    -   G.12 Method G or G.1-G.4 wherein the condition to be treated or        controlled is cerebral edema consequent to an epileptic seizure.    -   G.13 Method G or G.1-G.4 wherein the condition to be treated or        controlled is cerebral edema consequent to an infection.    -   G.14 Method G or G.1-G.4 wherein the condition to be treated or        controlled is cerebral edema consequent to a metabolic disorder.    -   G.15 Method G or G.1-G.4 wherein the condition to be treated or        controlled is cerebral edema consequent to glioma.    -   G.16 Method G or G.1-G.4 wherein the condition to be treated or        controlled is cerebral edema consequent to meningitis.    -   G.17 Method G or G.1-G.4 wherein the condition to be treated or        controlled is cerebral edema consequent to acute mountain        sickness.    -   G.18 Method G or G.1-G.4 wherein the condition to be treated or        controlled is cerebral edema consequent to water intoxication.    -   G.19 Method G or G.1-G.4 wherein the condition to be treated or        controlled is cerebral edema consequent to hepatic failure,        hepatic encephalopathy, or diabetic ketoacidosis.    -   G.20 Method G or G.1-G.3 wherein the condition to be treated or        controlled is cerebral edema consequent to an abscess.    -   G.21 Method G or G.1-G.3 wherein the condition to be treated or        controlled is cerebral edema consequent to eclampsia.    -   G.22 Method G or G.1-G.3 wherein the condition to be treated or        controlled is cerebral edema consequent to Creutzfeldt-Jakob        disease.    -   G.23 Method G or G.1-G.3 wherein the condition to be treated or        controlled is cerebral edema consequent to lupus cerebritis.    -   G.24 Method G or G.1-G.3 wherein the condition to be treated or        controlled is edema consequent to hypoxia, e.g., general        systemic hypoxia, e.g., hypoxia caused by an interruption of        blood perfusion, for example wherein the edema is cerebral edema        consequent to hypoxia caused by cardiac arrest, stroke, or other        interruption of blood perfusion to the brain, or wherein the        edema is cardiac edema consequent to cardiac ischemia or other        interruption of blood flow to the heart.    -   G.25 Method G or G.1-G.3 wherein the condition to be treated or        controlled is cerebral edema consequent to microgravity and/or        radiation exposure, e.g., exposure from space flight or from        working with radioactive materials or from working in        radioactive areas.    -   G.26 Method G or G.1-G.3 wherein the condition to be treated or        controlled is cerebral edema consequent to an invasive central        nervous system procedure, e.g., neurosurgery, endovascular clot        removal, spinal tap, aneurysm repair, or deep brain stimulation.    -   G.27 Method G.25 or G.26 wherein the patient is at elevated risk        of edema, e.g., due to microgravity and/or radiation exposure,        neurosurgery, endovascular clot removal, spinal tap, aneurysm        repair, or deep brain stimulation.    -   G.28 Method G.25 or G.26 wherein the patient already has edema.    -   G.29 Method G or G.1-G.28 wherein the edema is cytotoxic        cerebral edema or is primarily cytotoxic cerebral edema.    -   G.30 Method G, G.1-G.19, or G.24 wherein the edema is cytotoxic        cerebral edema or is primarily cytotoxic cerebral edema.    -   G.31 Method G, G.1, or G.2 wherein the condition to be treated        or controlled is spinal cord edema, e.g., spinal cord edema        consequent to a spinal cord trauma, e.g., spinal cord        compression.    -   G.32 Method G.31 wherein the condition to be treated or        controlled is spinal cord edema consequent to spinal cord        compression.    -   G.33 Method G, G.1, or G.2 wherein the condition to be treated        or controlled is optic nerve edema, e.g., optic nerve edema        consequent to microgravity and/or radiation exposure, e.g.,        exposure from space flight or from working with radioactive        materials or from working in radioactive areas.    -   G.34 Method G, G.1, or G.2 wherein the condition to be treated        or controlled is retinal edema.    -   G.35 Method G, G.1, or G.2 wherein the condition to be treated        or controlled is pulmonary edema.    -   G.36 Method G or G.1 wherein the condition to be treated or        controlled is epilepsy.    -   G.37 Method G or G.1 wherein the condition to be treated or        controlled is retinal ischemia or other diseases of the eye        associated with abnormalities in intraocular pressure and/or        tissue hydration.    -   G.38 Method G or G.1 wherein the condition to be treated or        controlled is myocardial ischemia.    -   G.39 Method G or G.1 wherein the condition to be treated or        controlled is myocardial ischemia/reperfusion injury.    -   G.40 Method G or G.1 wherein the condition to be treated or        controlled is myocardial infarction.    -   G.41 Method G or G.1 wherein the condition to be treated or        controlled is myocardial hypoxia.    -   G.42 Method G or G.1 wherein the condition to be treated or        controlled is congestive heart failure.    -   G.43 Method G or G.1 wherein the condition to be treated or        controlled is sepsis.    -   G.44 Method G or G.1 wherein the condition to be treated or        controlled is a migraine.    -   G.45 Method G or G.1 wherein the condition to be treated or        controlled is neuromyelitis optica.    -   G.46 Method G or G.1 wherein the condition to be treated or        controlled is glioblastoma.    -   G.47 Method G or G.1 wherein the condition to be treated or        controlled is fibromyalgia.    -   G.48 Method G or G.1 wherein the condition to be treated or        controlled is multiple sclerosis.    -   G.49 Method G wherein the aquaporin is AQP2.    -   G.50 Method G or G.49 wherein the condition to be treated or        controlled is hyponatremia or excessive fluid retention, e.g.,        consequent to heart failure (HF), for example congestive heart        failure, liver cirrhosis, nephrotic disorder, syndrome of        inappropriate antidiuretic hormone secretion (SIADH), or        infertility treatment.    -   G.51 Method G, G.49, or G.50 wherein the condition to be treated        or controlled is ovarian hyperstimulation syndrome.    -   G.52 Method G, G.49, or G.50 further comprising one or more of        restriction of dietary sodium, fluid and/or alcohol; and/or        administration of one or more diuretics, vasopressin receptor        antagonists, angiotensin converting enzyme (ACE) inhibitors,        aldosterone inhibitors, angiotensin receptor blockers (ARBs),        beta-adrenergic antagonists (beta-blockers), and/or digoxin.    -   G.53 Method G or G.1-G.52 wherein the prodrug salt of an        inhibitor of the aquaporin, e.g., the compound of Formula I,        e.g., the compound of 1.1-1.52, or, e.g., the compound of        Formula II, e.g., the compound of 2.1-2.26, is administered        orally.    -   G.54 Method G or G.1-G.52 wherein the prodrug salt of an        inhibitor of the aquaporin, e.g., the compound of Formula I,        e.g., the compound of 1.1-1.52, or, e.g., the compound of        Formula II, e.g., the compound of 2.1-2.26, is administered        parenterally.    -   G.55 Method G.54 wherein the prodrug salt of an inhibitor of the        aquaporin, e.g., the compound of Formula I, e.g., the compound        of 1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, is administered by injection, e.g.,        subcutaneously, intramuscularly, intravenously, or        intrathecally, e.g., a bolus injected subcutaneously,        intramuscularly, intravenously, or intrathecally.    -   G.56 Method G.55 wherein the prodrug salt of an inhibitor of the        aquaporin, e.g., the compound of Formula I, e.g., the compound        of 1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, is administered intravenously, e.g., IV        bolus and/or IV infusion, e.g., IV bolus followed by IV        infusion.    -   G.57 Method G or G.1-G.56 wherein the patient is human.    -   G.58 Method G or G.1-G.57 wherein the onset of action after        administration of the prodrug salt of an inhibitor of the        aquaporin, e.g., the compound of Formula 1, e.g., the compound        of 1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, is fairly rapid.

In yet another embodiment, provided is a compound of Formula I, e.g., acompound of 1.1-1.52, or, e.g., a compound of Formula II, e.g., acompound of 2.1-2.26, for use in treating or controlling a disease orcondition mediated by an aquaporin.

In yet another embodiment, provided is a compound of Formula I, e.g., acompound of 1.1-1.52, or, e.g., a compound of Formula II, e.g., acompound of 2.1-2.26, for use in any of Methods A, e.g., A.1-A.58, anyof Methods B, e.g., B.1-B.41, any of Methods C, e.g., C.1-C.8, any ofMethods D, e.g., D.1-D.19, any of Methods E, e.g., E.1-E.59, any ofMethods F, e.g., F.1-F.5, and any of Methods G, e.g., G.1-G.58.

In yet another embodiment, provided is a compound of Formula I, e.g., acompound of 1.1-1.52, or, e.g., a compound of Formula II, e.g., acompound of 2.1-2.26, in the manufacture of a medicament for treating orcontrolling a disease or condition mediated by an aquaporin.

In yet another embodiment, provided is a compound of Formula I, e.g., acompound of 1.1-1.52, or, e.g., a compound of Formula II, e.g., acompound of 2.1-2.26, in the manufacture of a medicament for use in anyof Methods A, e.g., A.1-A.58, any of Methods B, e.g., B.1-B.41, any ofMethods C, e.g., C.1-C.8, any of Methods D, e.g., D.1-D.19, any ofMethods E, e.g., E.1-E.59, any of Methods F, e.g., F.1-F.5, and any ofMethods G, e.g., G.1-G.58.

In yet another embodiment, provided is a pharmaceutical compositioncomprising a compound of Formula I, e.g., a compound of 1.1-1.52, or,e.g., a compound of Formula II, e.g., a compound of 2.1-2.26, incombination with a pharmaceutically acceptable excipient for use intreating or controlling a disease or condition mediated by an aquaporin.

In yet another embodiment, provided is a pharmaceutical compositioncomprising a compound of Formula I, e.g., a compound of 1.1-1.52, or,e.g., a compound of Formula II, e.g., a compound of 2.1-2.26, incombination with a pharmaceutically acceptable excipient for use in anyof Methods A, e.g., A.1-A.58, any of Methods B, e.g., B.1-B.41, any ofMethods C, e.g., C.1-C.8, any of Methods D, e.g., D.1-D.19, any ofMethods E, e.g., E.1-E.59, any of Methods F, e.g., F.1-F.5, and any ofMethods G, e.g., G.1-G.58.

Compounds of Formula I, e.g., compounds of 1.1-1.52, or, e.g., compoundsof Formula II, e.g., compounds of 2.1-2.26, as hereinbefore describedfor use in the methods of the invention may be used as a soletherapeutic agent, but may also be used in combination or forco-administration with other active agents, for example in conjunctionwith conventional therapies for cerebral edema, stroke, traumatic braininjury, glioma (e.g., glioblastoma), meningitis, acute mountainsickness, infection, metabolic disorder, hypoxia, water intoxication,hepatic failure, hepatic encephalopathy, diabetic ketoacidosis, abscess,eclampsia, Creutzfeldt-Jakob disease, lupus cerebritis, optic nerveedema, hyponatremia, fluid retention, ovarian hyperstimulation syndrome,epilepsy, retinal ischemia or other diseases of the eye associated withabnormalities in intraocular pressure and/or tissue hydration,myocardial ischemia, myocardial ischemia/reperfusion injury, myocardialinfarction, myocardial hypoxia, congestive heart failure, sepsis,neuromyelitis optica, or migraines.

A dose or method of administration of the dose of the present disclosureis not particularly limited. Dosages employed in practicing the presentdisclosure will of course vary depending, e.g. on the particular diseaseor condition to be treated, the particular compound used, the mode ofadministration, and the therapy desired. The compounds may beadministered by any suitable route, including orally, parenterally,transdermally, or by inhalation. In stroke or other severelydebilitating diseases or conditions, for example where the patient maybe unconscious or unable to swallow, an IV infusion and/or IV bolus maybe preferred. In general, satisfactory results, e.g. for the treatmentof diseases as hereinbefore set forth are indicated to be obtained onoral administration at dosages of the order from about 0.01 to 15.0mg/kg. In larger mammals, for example humans, an indicated daily dosagefor oral administration will accordingly be in the range of from about0.75 to 1000 mg per day, conveniently administered once, or in divideddoses 2 to 3 times, daily or in sustained release form. Unit dosageforms for oral administration thus for example may comprise from about0.2 to 75 or 150 mg, e.g. from about 0.2 or 2.0 mg to 50, 75, 100, 125,150 or 200 mg of a compound of Formula T, e.g., a compound of 1.1-1.52,or, e.g., a compound of Formula II, e.g., a compound of 2.1-2.26,together with a pharmaceutically acceptable diluent or carrier therefor.When the medicament is used via injection (subcutaneously,intramuscularly or intravenously) the dose may be 0.1 or 0.25 mg to 500mg per day, e.g., from about 0.25 to 75 or 150 mg, e.g., from about 0.1or 0.25 or 2.0 mg to 50, 75, 100, 125, 150, 200, 300, 400, or 500 mg, bybolus or if IV by bolus or infusion.

In yet another embodiment, provided is a pharmaceutical composition(Composition I) comprising a compound of Formula I, e.g., a compound of1.1-1.52, or, e.g., a compound of Formula II, e.g., a compound of2.1-2.26, and a pharmaceutically acceptable excipient.

Further provided is Composition I as follows:

-   -   1.1 Composition I wherein the composition comprises 0.1 or 0.25        mg to 2.0 g of the compound of Formula I, e.g., the compound of        1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, e.g., from about 0.1 or 0.25 mg to 75 mg        or 600 mg, e.g., from about 0.1 or 0.25 or 1 or 2 mg or 5 or 10        or 15 or 20 to 50, 75, 100, 125, 150, 200, 300, 400, 500, or 600        mg, or 1 g, 1.5 g, or 2.0 g, e.g., from about 5 to 50, 75, 100,        125, 150, 200, 300, 400, 500, or 600 mg, or 1 g, 1.5 g, or 2 g,        e.g., from about 5 to 500 mg, e.g., from about 5 to 300 mg,        e.g., from about 5 to 200 mg, e.g., from about 25 to 500 mg,        e.g., from about 25 to 300 mg, e.g., from about 25 to 200 mg,        e.g., from about 0.5 or 1 mg to 50 mg, e.g., from about 0.5 or 1        mg to 20 mg, e.g., from about 0.5 or 1 mg to 10 mg, e.g., from        about 1 or 2 or 5 mg to 10 or 20 mg, e.g., from about 1 or 2 or        3 or 4 to 5 mg or wherein the composition comprises the compound        of Formula I, e.g., the compound of 1.1-1.52, or, e.g., the        compound of Formula II, e.g., the compound of 2.1-2.26 in an        amount sufficient to provide 0.1 or 0.25 mg to 2.0 g of        N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,        e.g., from about 0.1 or 0.25 mg to 75 or 600 mg, e.g., from        about 0.1 or 0.25 or 1 or 2 or 5 or 10 or 15 or 20 mg to 50, 75,        100, 125, 150, 200, 300, 400, 500, or 600 mg, or 1 g, 1.5 g, or        2.0 g, e.g., from about 5 to 50, 75, 100, 125, 150, 200, 300,        400, 500, or 600 mg, or 1 g, 1.5 g, or 2 g, e.g., from about 5        to 500 mg, e.g., from about 5 to 300 mg, e.g., from about 5 to        200 mg, e.g., from about 25 to 500 mg, e.g., from about 25 to        300 mg, e.g., from about 25 to 200 mg, e.g., from about 0.5 or 1        mg to 50 mg, e.g., from about 0.5 or 1 mg to 20 mg, e.g., from        about 0.5 or 1 mg to 10 mg, e.g., from about 1 or 2 or 5 mg to        10 or 20 mg, e.g., from about 1 or 2 or 3 or 4 to 5 mg.    -   1.2 Composition I wherein the composition comprises        2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl        dihydrogen phosphate in an amount sufficient to provide a dose        of 0.01 or 0.1 or 0.5 mg/kg to 1 or 5 or 10 or 15 mg/kg of        N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,        e.g., a dose of about 0.05 to 1 or 5 mg/kg, e.g., a dose of        about 0.05 to 0.1, 0.2, 0.3, 0.4, 0.5, 1, 5, 10 or 20 mg/kg,        e.g., a dose of about 0.5 to 1, 2, 3, 4, 5 or 10 or 20 mg/kg,        e.g., a dose of about 1 to 2, 3, 4, 5, 10, 20 or 50 mg/kg.    -   1.3 Composition I, 1.1, or 1.2 wherein the pharmaceutically        acceptable excipient comprises one or more buffering agents        which may control pH, e.g., one or more of sodium citrate,        potassium citrate, sodium phosphate (e.g., NaH₂PO₄ and/or        Na₂HPO₄), potassium phosphate (e.g., KH₂PO₄ and/or K₂HPO₄),        tris(hydroxymethyl)aminomethane (also known as tris base),        tris(hydroxymethyl)aminomethane acetate (also known as tris        acetate), zinc chloride, meglumine, sodium acetate, potassium        acetate, sodium hydroxide, and arginine, e.g., one or more of        sodium citrate, Na₂HPO₄, tris(hydroxymethyl)aminomethane,        tris(hydroxymethyl)aminomethane acetate e.g., Na₂HPO₄, e.g.,        tris(hydroxymethyl)aminomethane, e.g.,        tris(hydroxymethyl)aminomethane acetate.    -   1.4 Composition I or 1.1-1.3 wherein the composition comprises 1        or 5 mg to 200 or 500 mg of one or more buffering agents, e.g.,        from about 1 or 5 or 10 mg to 50, 100, 150, 200, 250, 300, 350,        400, 450, or 500 mg.    -   1.5 Composition I or 1.1-1.4 wherein the composition comprises        one or more of sodium citrate and sodium phosphate, e.g.,        Na₂HPO₄.    -   1.6 Composition I or 1.1-1.5 wherein the composition comprises        sodium citrate.    -   1.7 Composition 1.6 wherein the composition comprises 1 or 5 mg        to 200 or 500 mg sodium citrate, e.g., from about 1 or 5 or 10        mg to 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg        sodium citrate.    -   1.8 Composition I or 1.1-1.7 wherein the composition comprises        sodium phosphate, e.g., Na₂HPO₄.    -   1.9 Composition 1.8 wherein the composition comprises 1 or 5 mg        to 200 or 500 mg sodium phosphate, e.g., from about 1 or 5 or 10        mg to 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg        sodium phosphate, e.g., Na₂HPO₄.    -   1.10 Composition I or 1.1-1.9 wherein the composition comprises        Na₂HPO₄.    -   1.11 Composition 1.10 wherein the composition comprises 1 or 5        mg to 200 mg or 500 mg Na₂HPO₄, e.g., from about 1 or 5 or 10 mg        to 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg        Na₂HPO₄.    -   1.12 Composition I or 1.1-1.11 wherein the composition comprises        one or more bulking agents which may provide an adequate        structure to the lyophilized cake, e.g., one or more of        mannitol, lactose, sucrose, trehalose, sorbitol, glucose,        raffinose, arginine, glycine, histidine, dextran (e.g., dextran        40), polyvinylpyrrolidone, polyethylene glycol, and        polypropylene glycol, e.g., one or more of mannitol, glucose,        sucrose, lactose, trehalose, and dextran (e.g., dextran 40).    -   1.13 Composition I or 1.1-1.12 wherein the composition comprises        5 or 10 or 50 mg to 2 or 5 g of one or more bulking agents,        e.g., from about 50 or 100 mg to 200, 300, 500, or 800 mg, or 1,        1.5, 2, 3, 4, or 5 g of one or more bulking agents.    -   1.14 Composition I or 1.1-1.13 wherein the composition comprises        dextran (e.g., dextran 40).    -   1.15 Composition 1.14 wherein the composition comprises 5 or 10        or 50 mg to 2 or 5 g dextran (e.g., dextran 40), e.g., from        about 50 or 100 mg to 200, 300, 500, or 800 mg, or 1, 1.5, 2, 3,        4, or 5 g dextran (e.g., dextran 40).    -   1.16 Composition I or 1.1-1.15 wherein the composition comprises        one or more solubilizing agents, e.g., ethylenediamine        tetraacetic acid (EDTA) or a salt thereof (e.g., calcium        disodium EDTA, disodium EDTA, sodium EDTA), alpha cyclodextrin,        hydroxypropyl-β-cyclodextrin, polysorbate 80, tert-butanol,        isopropanol, dichloromethane, ethanol, acetone, and glycerol;        one or more collapse temperature modifiers which may shift the        overall collapse temperature higher, e.g., one or more of        dextran, Ficoll®, gelatin, and hydroxyethyl starch; one or more        tonicity modifiers, e.g., one or more of sodium chloride,        potassium chloride, sucrose, mannitol, glucose, and lactose; and        one or more antimicrobial agents, e.g., one or more of benzyl        alcohol, phenol, 2-phenoxyethanol, m-cresol, chlorobutanol,        parabens (e.g., methyl paraben, ethyl paraben, propyl paraben),        benzalkonium chloride, benzethonium chloride, myristyl        gamma-picolinium salt (e.g., myristyl gamma-picolinium        chloride), and organomercury compounds and salts (e.g., phenyl        mercuric acetate, phenyl mercuric borate, phenyl mercuric        nitrate, and thimerosal).    -   1.17 Composition I or 1.1-1.16 wherein the composition is a        solid.    -   1.18 Composition I or 1.1-1.17 wherein the composition is        lyophilized.    -   1.19 Composition I or 1.1-1.18 wherein the compound of Formula        I, e.g., the compound of 1.1-1.52, or, e.g., the compound of        Formula II, e.g., the compound of 2.1-2.26, is lyophilized,        e.g., by freezing, primary drying, and secondary drying.    -   1.20 Composition 1.19 wherein the compound of Formula 1, e.g.,        the compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, is lyophilized, e.g., by        freezing, primary drying, and secondary drying, prior to        admixture with the pharmaceutically acceptable excipient.    -   1.21 Composition I or 1.1-1.20 wherein the compound of Formula        I, e.g., the compound of 1.1-1.52, or, e.g., the compound of        Formula II, e.g., the compound of 2.1-2.26, is crystalline.    -   1.22 Composition I or 1.1-1.20 wherein the compound of Formula        I, e.g., the compound of 1.1-1.52, or, e.g., the compound of        Formula II, e.g., the compound of 2.1-2.26, is amorphous.    -   1.23 Composition I or 1.1-1.22 which is suitable for        constitution, or reconstitution if lyophilized, with a solvent        into a pharmaceutically acceptable liquid (e.g., a solution or        suspension, e.g., a solution).    -   1.24 Composition I or 1.1-1.23 wherein the composition is        admixed with a solvent, e.g., a sterile solution, e.g., sterile        water for injection, a sterile solution comprising dextrose        (e.g., dextrose injection 5%), a sterile solution comprising        sodium chloride (e.g., 0.9% sodium chloride injection), a        sterile solution comprising benzyl alcohol (e.g., bacteriostatic        water for injection with benzyl alcohol or bacteriostatic sodium        chloride for injection with benzyl alcohol), or Lactated        Ringer's.    -   1.25 Composition I or 1.1-1.24 wherein the composition is        admixed with 0.5 to 500 mL solvent, e.g., from about 1 or 2 mL        to 500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 50, 75, 100,        150, 200, 300 or 500 mL, e.g., from about 1 or 2 mL to 5, 10,        25, 50, 75, 100, or 200 mL, e.g., from about 5 to 10, 25, 50, or        100 mL.    -   1.26 Composition I or 1.1-1.25 wherein the composition is        admixed with 0.5 to 500 mL sterile solution, e.g., sterile water        for injection, a sterile solution comprising dextrose (e.g.,        dextrose injection 5%), a sterile solution comprising sodium        chloride (e.g., 0.9% sodium chloride injection), a sterile        solution comprising benzyl alcohol (e.g., bacteriostatic water        for injection with benzyl alcohol or bacteriostatic sodium        chloride for injection with benzyl alcohol), or Lactated        Ringer's, e.g., from about 1 or 2 mL to 500 mL, e.g., from about        1 or 2 mL to 5, 10, 25, 50, 75, 100, 150, 200, 300 or 500 mL,        e.g., from about 1 or 2 mL to 5, 10, 25, 50, 75, 100, or 200 mL,        e.g., from about 5 to 10, 25, 50, or 100 mL.    -   1.27 Composition I or 1.1-1.26 wherein the composition is        admixed with sterile water for injection or a sterile solution        comprising sodium chloride (e.g., 0.9% sodium chloride        injection).    -   1.28 Composition I or 1.1-1.27 wherein the composition is        admixed with sterile water for injection.    -   1.29 Composition 1.28 wherein the composition is admixed with        0.5 to 500 mL sterile water for injection, e.g., from about 1 or        2 mL to 500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 50, 75,        100, 150, 200, 300 or 500 mL, e.g., from about 1 or 2 to 5, 10,        25, 50, 75, 100, or 200 mL, e.g., from about 5 to 10, 25, 50, or        100 mL.    -   1.30 Composition I or 1.1-1.29 wherein the composition is        admixed with a sterile solution comprising sodium chloride        (e.g., 0.9% sodium chloride injection).    -   1.31 Composition 1.30 wherein the composition is admixed with        0.5 to 500 mL a sterile solution comprising sodium chloride        (e.g., 0.9% sodium chloride injection), e.g., from about 1 of 2        mL to 500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 50, 75,        100, 150, 200, 300 or 500 mL, e.g., from about 1 or 2 to 5, 10,        25, 50, 75, 100, or 200 mL, e.g., from about 5 to 10, 25, 50, or        100 mL.    -   1.32 Composition 1.24-1.31 wherein the solvent, e.g., the        sterile solution, comprises a buffering agent, e.g., one or more        of sodium citrate, potassium citrate, sodium phosphate (e.g.,        NaH₂PO₄ and/or Na₂HPO₄), potassium phosphate (e.g., KH₂PO₄        and/or K₂HPO₄), tris base (also known as        tris(hydroxymethyl)aminomethane), tris acetate (also known as        tris(hydroxymethyl)aminomethane acetate), zinc chloride,        meglumine, sodium acetate, potassium acetate, sodium hydroxide,        and arginine, e.g., one or more of sodium citrate and Na₂HPO₄,        e.g., Na₂HPO₄.    -   1.33 Composition 1.32 wherein the solvent, e.g., the sterile        solution, comprises 1 or 5 mg to 200 or 500 mg of one or more        buffering agents, e.g., from about 1 or 5 or 10 mg to 50, 100,        150, 200, 250, 300, 350, 400, 450, or 500 mg.    -   1.34 Composition 1.32 or 1.33 wherein the solvent, e.g. the        sterile solution, comprises one or more of sodium citrate and        sodium phosphate, e.g., Na₂HPO₄.    -   1.35 Composition 1.32-1.34 wherein the solvent, e.g. the sterile        solution comprises sodium citrate.    -   1.36 Composition 1.35 wherein the solvent, e.g., the sterile        solution, comprises 1 or 5 mg to 200 or 500 mg sodium citrate,        e.g., from about 1 or 5 or 10 mg to 50, 100, 150, 200, 250, 300,        350, 400, 450, or 500 mg sodium citrate.    -   1.37 Composition 1.31-1.36 wherein the solvent, e.g., the        sterile solution, comprises sodium phosphate, e.g., Na₂HPO₄.    -   1.38 Composition 1.37 wherein the solvent, e.g., the sterile        solution, comprises 1 or 5 mg to 200 mg or 500 mg sodium        phosphate, e.g., from about 1 or 5 or 10 mg to 50, 100, 150,        200, 250, 300, 350, 400, 450, or 500 mg sodium phosphate, e.g.,        Na₂HPO₄.    -   1.39 Composition 1.24-1.38 wherein the solvent, e.g., the        sterile solution comprises one or more bulking agents, e.g., one        or more of maltose, mannose, ribose, cyclodextrin, mannitol,        lactose, sucrose, trehalose, sorbitol, glucose, raffinose,        arginine, glycine, histidine, dextran (e.g., dextran 40),        polyvinylpyrrolidone, polyethylene glycol, and polypropylene        glycol, e.g., one or more of mannitol, glucose, sucrose,        lactose, trehalose, and dextran (e.g., dextran 40).    -   1.40 Composition 1.24-1.39 wherein the solvent, e.g., the        sterile solution, comprises 5 or 10 or 50 mg to 2 or 5 g of one        or more bulking agents, e.g., from about 50 or 100 mg to 200,        300, 500, or 800 mg, or 1, 1.5, 2, 3, 4, or 5 g of one or more        bulking agents.    -   1.41 Composition 1.24-1.40 wherein the solvent, e.g., the        sterile solution, comprises dextran (e.g., dextran 40).    -   1.42 Composition 1.41 wherein the solvent, e.g. the sterile        solution, comprises 5 or 10 or 50 mg to 2 or 5 g dextran (e.g.,        dextran 40), e.g., from about 50 or 100 mg to 200, 300, 500, or        800 mg, or 1, 1.5, 2, 3, 4, or 5 dextran (e.g., dextran 40).    -   1.43 Composition 1.24-1.42 wherein the solvent, e.g., the        sterile solution, comprises one or more solubilizing agents,        e.g., ethylenediamine tetraacetic acid (EDTA) or a salt thereof        (e.g., calcium disodium EDTA, disodium EDTA, sodium EDTA), alpha        cyclodextrin, hydroxypropyl-β-cyclodextrin, polysorbate 80,        tert-butanol, isopropanol, dichloromethane, ethanol, acetone,        and glycerol; one or more collapse temperature modifiers which        may shift the overall collapse temperature higher, e.g., one or        more of dextran, Ficoll®, gelatin, and hydroxyethyl starch; one        or more tonicity modifiers, e.g., one or more of sodium        chloride, potassium chloride, sucrose, mannitol, and glucose;        and one or more antimicrobial agents, e.g., one or more of        benzyl alcohol, phenol, 2-phenoxyethanol, m-cresol,        chlorobutanol, parabens (e.g., methyl paraben, ethyl paraben,        propyl paraben), benzalkonium chloride, benzethonium chloride,        myristyl gamma-picolinium salt (e.g., myristyl gamma-picolinium        chloride), and organomercury compounds and salts (e.g., phenyl        mercuric acetate, phenyl mercuric borate, phenyl mercuric        nitrate, and thimerosal).    -   1.44 Composition 1.24-1.43 wherein the pH is between pH 7 and pH        10.5, e.g., between pH 7 and pH 9.5, e.g., between pH 7 and pH        8.    -   1.45 Composition 1.24-1.44 wherein the composition is filtered        to remove particles and microbes, e.g., filtered prior to        injection.    -   1.46 Composition 1.24-1.45 wherein the compositions is        administered about 24 hours, 12 hours, 10 hours, 8 hours, 2        hours, 1 hour, 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5        minutes, 3 minutes, 2 minutes or 1 minute or less after        admixture.    -   1.47 Composition I or 1.1-1.46 wherein the composition is for        injection, e.g., subcutaneously, intramuscularly, intravenously,        or intrathecally, e.g., intramuscularly or intravenously, e.g.,        a bolus injected subcutaneously, intramuscularly, intravenously,        or intrathecally.    -   1.48 Composition 1.47 wherein the composition is for injection        intravenously, e.g., IV bolus and/or IV infusion, e.g., IV bolus        followed by IV infusion.    -   1.49 Composition 1.47 wherein the composition is for injection        intramuscularly, e.g., IM bolus and/or IM infusion, e.g., IM        bolus followed by IM infusion.    -   1.50 Composition 1.48 or 1.49 wherein the infusion, e.g., IV or        IM, is administered over about 10 or 30 minutes to 72 hours,        e.g., about 30 minutes to 24 hours, e.g., about 30 minutes to 12        hours, e.g., about 30 minutes to 8 hours, e.g., about 30 minutes        to 6 hours, e.g., about 30 minutes to 4 hours, e.g., about 30        minutes to 2 hours, e.g., about 30 minutes to 1 hour, e.g.,        about 72 hours.    -   1.51 Composition I wherein the composition is formulated for        oral administration.    -   1.52 Composition 1.51 wherein the composition is a tablet,        capsule, solution, suspension, or the like.    -   1.53 Composition I or 1.1-1.52 wherein the composition comprises        one or more additional therapeutic agents, e.g., one or more        additional therapeutic agents for cerebral edema, stroke,        traumatic brain injury, glioma (e.g., glioblastoma), meningitis,        acute mountain sickness, infection, metabolic disorder, hypoxia,        water intoxication, hepatic failure, hepatic encephalopathy,        diabetic ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob        disease, lupus cerebritis, optic nerve edema, hyponatremia,        fluid retention, ovarian hyperstimulation syndrome, epilepsy,        retinal ischemia or other diseases of the eye associated with        abnormalities in intraocular pressure and/or tissue hydration,        myocardial ischemia, myocardial ischemia/reperfusion injury,        myocardial infarction, myocardial hypoxia, congestive heart        failure, sepsis, neuromyelitis optica, or migraines.    -   1.54 Composition I or 1.1-1.53 wherein the composition comprises        one or more additional therapeutic agents, e.g., one or more        additional therapeutic agents for pulmonary edema, fibromyalgia,        or multiple sclerosis.    -   1.55 Composition I or 1.1-1.54 wherein the composition is        administered concurrently or sequentially, in either order, with        one or more additional therapeutic agents, e.g., one or more        additional therapeutic agents for cerebral edema, stroke,        traumatic brain injury, glioma (e.g., glioblastoma), meningitis,        acute mountain sickness, infection, metabolic disorder, hypoxia,        water intoxication, hepatic failure, hepatic encephalopathy,        diabetic ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob        disease, lupus cerebritis, optic nerve edema, hyponatremia,        fluid retention, ovarian hyperstimulation syndrome, epilepsy,        retinal ischemia or other diseases of the eye associated with        abnormalities in intraocular pressure and/or tissue hydration,        myocardial ischemia, myocardial ischemia/reperfusion injury,        myocardial infarction, myocardial hypoxia, congestive heart        failure, sepsis, neuromyelitis optica, or migraines.    -   1.56 Composition I or 1.1-1.55 wherein the composition is        administered concurrently or sequentially, in either order, with        one or more additional therapeutic agents, e.g., one or more        additional therapeutic agents for pulmonary edema, fibromyalgia,        or multiple sclerosis.    -   1.57 Composition I or 1.1-1.57 wherein the composition for use        in any of the methods described herein, e.g., for use in Method        A, e.g., Method A.1-A.58, for use in Method B, e.g., Method        B.1-B.41, e.g., for use in Method C, e.g., C.1-C.8, e.g., for        use in Method D, e.g., D.1-D.19, e.g., for use in Method E,        e.g., E.1-E.59, e.g., for use in Method F, e.g., F.1-F.5, e.g.,        for use in Method G, e.g., G.1-G.58.

In some embodiments, when the compound of Formula I, e.g., the compoundof 1.1-1.52, or, e.g., the compound of Formula II, e.g., the compound of2.1-2.26, is provided as a solid that is to be admixed with a solvent,e.g., a sterile solution, to provide a pharmaceutically acceptableliquid, it is typically provided as a powder and admixed immediately orshortly before administration to the patient. In some embodiments, thepowdered compound of Formula I, e.g., the compound of 1.1-1.52, or,e.g., the compound of Formula II, e.g., the compound of 2.1-2.26, may bepackaged in a container, for example, in a vial to which is added thesolvent. Alternatively, the contents of the vial may be added to thesolvent in a separate container. In some embodiments, the powdered thecompound of Formula I, e.g., the compound of 1.1-1.52, or, e.g., thecompound of Formula II, e.g., the compound of 2.1-2.26, is packaged in asachet, such as a foil package, that can be opened and the contentsadded to the solvent. In some embodiments, the powdered compound ofFormula I, e.g., the compound of 1.1-1.52, or, e.g., the compound ofFormula II, e.g., the compound of 2.1-2.26, is formulated as a tabletthat dissolves when it is added to the solvent.

In yet another embodiment, a pharmaceutical composition comprising acompound of Formula I, e.g., a compound of 1.1-1.52, or, e.g., acompound of Formula II, e.g., a compound of 2.1-2.26, e.g., CompositionI, e.g., composition 1.1-1.52, is prepared by admixing the compound ofFormula I, e.g., the compound of 1.1-1.52, or, e.g., the compound ofFormula II, e.g., the compound of 2.1-2.26, with a pharmaceuticallyacceptable excipient. In some embodiments, the compound of Formula 1,e.g., the compound of 1.1-1.52, or, e.g., the compound of Formula II,e.g., the compound of 2.1-2.26, is crystalline. In some embodiments, thecompound of Formula I, e.g., the compound of 1.1-1.52, or, e.g., thecompound of Formula II, e.g., the compound of 2.1-2.26, is amorphous. Insome embodiments, the compound of Formula I, e.g., the compound of1.1-1.52, or, e.g., the compound of Formula II, e.g., the compound of2.1-2.26, is lyophilized. In some embodiments, the compound of FormulaI, e.g., the compound of 1.1-1.52, or, e.g., the compound of Formula II,e.g., the compound of 2.1-2.26, and the pharmaceutically acceptableexcipient, e.g., Composition I, e.g., composition 1.1-1.57, islyophilized.

In yet another embodiment, a pharmaceutical composition comprising acompound of Formula I, e.g., a compound of 1.1-1.52, or, e.g., acompound of Formula II, e.g., a compound of 2.1-2.26, e.g., CompositionI, e.g., composition 1.1-1.57, is prepared by admixing the compound ofFormula I, e.g., the compound of 1.1-1.52, or, e.g., the compound ofFormula II, e.g., the compound of 2.1-2.26, with a sterile solution,e.g., sterile water for injection or a sterile solution comprisingsodium chloride (e.g., 0.9% sodium chloride injection), to form apharmaceutically acceptable liquid. In some embodiments, the compound ofFormula I, e.g., the compound of 1.1-1.52, or, e.g., the compound ofFormula II, e.g., the compound of 2.1-2.26, is admixed with the sterilesolution immediately or shortly before administration. In someembodiments, the compound of Formula I, e.g., the compound of 1.1-1.52,or, e.g., the compound of Formula II, e.g., the compound of 2.1-2.26, isadmixed with a buffering agent, e.g., sodium citrate and/or sodiumphosphate (e.g., Na₂HPO₄), prior to admixture with the sterile solution,e.g., sterile water for injection or a sterile solution comprisingsodium chloride (e.g., 0.9% sodium chloride injection). In someembodiments, the compound of Formula I, e.g., the compound of 1.1-1.52,or, e.g., the compound of Formula II, e.g., the compound of 2.1-2.26, isadmixed with a buffering agent, e.g., sodium citrate and/or sodiumphosphate (e.g., Na₂HPO₄), and/or a bulking agent, e.g., dextran (e.g.,dextran 40), prior to admixture with the sterile solution, e.g., sterilewater for injection or a sterile solution comprising sodium chloride(e.g., 0.9% sodium chloride injection). In some embodiments, thecompound of Formula I, e.g., the compound of 1.1-1.52, or, e.g., thecompound of Formula II, e.g., the compound of 2.1-2.26, admixed with thebuffering agent and/or the bulking agent is lyophilized. In someembodiments, the compound of Formula I, e.g., the compound of 1.1-1.52,or, e.g., the compound of Formula II, e.g., the compound of 2.1-2.26, isadmixed with a sterile solution comprising a buffering agent, e.g.,sodium citrate and/or sodium phosphate (e.g., Na₂HPO₄). In someembodiments, the compound of Formula I, e.g., the compound of 1.1-1.52,or, e.g., the compound of Formula II, e.g., the compound of 2.1-2.26, isadmixed with a sterile solution comprising a buffering agent, e.g.,sodium citrate and/or sodium phosphate (e.g., Na₂HPO₄) and/or a bulkingagent. In some embodiments, the admixture of the compound of Formula I,e.g., the compound of 1.1-1.52, or, e.g., the compound of Formula II,e.g., the compound of 2.1-2.26, and the sterile solution is agitated,e.g., any mode of agitation that results in a clear liquid, e.g.,mechanical agitation, sonication, conventional mixing, conventionalstirring and the combinations thereof. In some embodiments, the compoundof Formula I, e.g., the compound of 1.1-1.52, or, e.g., the compound ofFormula II, e.g., the compound of 2.1-2.26, admixed with the sterilesolution is lyophilized. In some embodiments, the compound of Formula I,e.g., the compound of 1.1-1.52, or, e.g., the compound of Formula II,e.g., the compound of 2.1-2.26, admixed with the sterile solution iscrystalline. In some embodiments, the compound of Formula 1, e.g., thecompound of 1.1-1.52, or, e.g., the compound of Formula II, e.g., thecompound of 2.1-2.26, admixed with the sterile solution is amorphous.

In one embodiment, Composition I, e.g., composition 1.1-1.57, isprepared by admixing the compound of Formula I, e.g., the compound of1.1-1.52, or, e.g., the compound of Formula II, e.g., the compound of2.1-2.26, with a solvent, e.g., a sterile water for injection or asterile solution comprising sodium chloride (e.g., 0.9% sodium chlorideinjection). In some embodiments, the compound of Formula I, e.g., thecompound of 1.1-1.52, or, e.g., the compound of Formula II, e.g., thecompound of 2.1-2.26, is admixed with a buffering agent, e.g., sodiumcitrate and/or sodium phosphate (e.g., Na₂HPO₄), and/or a bulking agent,e.g., dextran (e.g., dextran 40), prior to admixture with the solvent.In some embodiments, the solvent comprises a buffering agent, e.g.,sodium citrate and/or sodium phosphate (e.g., Na₂HPO₄) and/or a bulkingagent, e.g., dextran (e.g., dextran 40). In some embodiments, theadmixture of the compound of Formula I, e.g., the compound of 1.1-1.52,or, e.g., the compound of Formula II, e.g., the compound of 2.1-2.26,and the solvent is agitated after admixture, e.g., by any mode ofagitation that results in a clear liquid, e.g., mechanical agitation,sonication, conventional mixing, conventional stirring and thecombinations thereof. In some embodiments, the compound of Formula 1,e.g., the compound of 1.1-1.52, or, e.g., the compound of Formula II,e.g., the compound of 2.1-2.26, is lyophilized. In some embodiments, theadmixture of the compound of Formula I, e.g., the compound of 1.1-1.52,or, e.g., the compound of Formula II, e.g., the compound of 2.1-2.26,and the buffering agent and/or bulking agent is lyophilized. In someembodiments, the compound of Formula I, e.g., the compound of 1.1-1.52,or, e.g., the compound of Formula II, e.g., the compound of 2.1-2.26, isadmixed with the solvent, e.g., the sterile solution, immediately orshortly before administration.

Pharmaceutical compositions disclosed herein, e.g., Composition I, e.g.,composition 1.1-1.57, may be contained in a sterilized vessel such assyringes, vials or ampoules of various sizes and capacities.

In yet another embodiment, provided is a kit (Kit I) comprising acompound of Formula I, e.g., a compound of 1.1-1.52, or, e.g., acompound of Formula II, e.g., a compound of 2.1-2.26.

Further provided is Kit I as follows:

-   -   1.1 Kit I wherein the kit comprises 0.1 or 0.25 mg to 2.0 g of        the compound of Formula 1, e.g., the compound of 1.1-1.52, or,        e.g., the compound of Formula II, e.g., the compound of        2.1-2.26, e.g., from about 0.1 or 0.25 mg to 75 or 600 mg, e.g.,        from about 0.1 or 0.25 or 1 or 2 or 5 or 10 or 15 or 20 mg to        50, 75, 100, 125, 150, 200, 300, 400, 500, or 600 mg, or 1, 1.5,        or 2.0 g, e.g., from about 5 to 50, 75, 100, 125, 150, 200, 300,        400, 500, or 600 mg, or 1 g, 1.5 g, or 2 g, e.g., from about 5        to 500 mg, e.g., from about 5 to 300 mg, e.g., from about 5 to        200 mg, e.g., from about 25 to 500 mg, e.g., from about 25 to        300 mg, e.g., from about 25 to 200 mg, e.g., from about 0.5 or 1        mg to 50 mg, e.g., from about 0.5 or 1 mg to 20 mg, e.g., from        about 0.5 or 1 mg to 10 mg, e.g., from about 1 or 2 or 5 mg to        10 or 20 mg, e.g., from about 1 or 2 or 3 or 4 to 5 mg or        wherein the composition comprises the compound of Formula I,        e.g., the compound of 1.1-1.52, or, e.g., the compound of        Formula II, e.g., the compound of 2.1-2.26 in an amount        sufficient to provide 0.1 or 0.25 mg to 2.0 g of        N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,        e.g., from about 0.1 or 0.25 mg to 75 or 600 mg, e.g., from        about 0.1 or 0.25 or 1 or 2 or 5 or 10 or 15 or 20 mg to 50, 75,        100, 125, 150, 200, 300, 400, 500, or 600 mg, or 1 g, 1.5 g, or        2.0 g, e.g., from about 5 to 50, 75, 100, 125, 150, 200, 300,        400, 500, or 600 mg, or 1 g, 1.5 g, or 2 g, e.g., from about 5        to 500 mg, e.g., from about 5 to 300 mg, e.g., from about 5 to        200 mg, e.g., from about 25 to 500 mg, e.g., from about 25 to        300 mg, e.g., from about 25 to 200 mg, e.g., from about 0.5 or 1        mg to 50 mg, e.g., from about 0.5 or 1 mg to 20 mg, e.g., from        about 0.5 or 1 mg to 10 mg, e.g., from about 1 or 2 or 5 mg to        10 or 20 mg, e.g., from about 1 or 2 or 3 or 4 to 5 mg.    -   1.2 Kit I or 1.1 wherein the kit comprises        2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl        dihydrogen phosphate in an amount sufficient to provide a dose        of 0.01 or 0.1 or 0.5 mg/kg to 1 or 5 or 10 or 15 mg/kg of        N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,        e.g., a dose of about 0.05 to 1 or 5 mg/kg, e.g., a dose of        about 0.05 to 0.1, 0.2, 0.3, 0.4, 0.5, 1, 5, 10 or 20 mg/kg,        e.g., a dose of about 0.5 to 1, 2, 3, 4, 5 or 10 or 20 mg/kg,        e.g., a dose of about 1 to 2, 3, 4, 5, 10, 20 or 50 mg/kg.    -   1.3 Kit I, 1.1, or 1.2 wherein the kit comprises one or more        pharmaceutically acceptable excipients.    -   1.4 Kit 1.3 wherein the one or more pharmaceutically acceptable        excipients are selected from the group consisting of buffering        agents, bulking agents, solubilizing agents, collapse        temperature modifiers and.    -   1.5 Kit 1.3 or 1.4 wherein the kit comprises one or more        buffering agents which may control pH, e.g., one or more of        sodium citrate, potassium citrate, sodium phosphate (e.g.,        NaH₂PO₄ and/or Na₂HPO₄), potassium phosphate (e.g., KH₂PO₄        and/or K₂HPO₄), tris(hydroxymethyl)aminomethane (also known as        tris base), tris(hydroxymethyl)aminomethane acetate (also known        as tris acetate), zinc chloride, meglumine, sodium acetate,        potassium acetate, sodium hydroxide, and arginine, e.g., one or        more of sodium citrate, Na₂HPO₄,        tris(hydroxymethyl)aminomethane, and        tris(hydroxymethyl)aminomethane acetate, e.g., Na₂HPO₄, e.g.,        tris(hydroxymethyl)aminomethane, e.g.,        tris(hydroxymethyl)aminomethane acetate.    -   1.6 Kit 1.5 wherein the kit comprises 1 or 5 mg to 200 mg or 500        mg of one or more buffering agents, e.g., from about 1 or 5 or        10 mg to 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.    -   1.7 Kit 1.5 or 1.6 wherein the kit comprises one or more of        sodium citrate and sodium phosphate, e.g., Na₂HPO₄.    -   1.8 Kit 1.3-1.7 wherein the kit comprises sodium citrate.    -   1.9 Kit 1.8 wherein the kit comprises 1 or 5 mg to 200 or 500 mg        sodium citrate, e.g., from about 1 or 5 or 10 mg to 50, 100,        150, 200, 250, 300, 350, 400, 450, or 500 mg sodium citrate.    -   1.10 Kit 1.3-1.9 wherein the kit comprises sodium phosphate,        e.g., Na₂HPO₄.    -   1.11 Kit 1.9 wherein the kit comprises 1 or 5 mg to 200 or 500        mg sodium phosphate, e.g., from about 1 or 5 or 10 mg to 50,        100, 150, 200, 250, 300, 350, 400, 450, or 500 mg sodium        phosphate, e.g., Na₂HPO₄.    -   1.12 Kit 1.3-1.10 wherein the kit comprises Na₂HPO₄.    -   1.13 Kit 1.12 wherein the kit comprises 1 or 5 mg to 200 or 500        mg Na₂HPO₄, e.g., from about 1 or 5 or 10 mg to 50, 100, 150,        200, 250, 300, 350, 400, 450, or 500 mg Na₂HPO₄.    -   1.14 Kit 1.3-1.13 wherein the kit comprises one or more bulking        agents which may provide an adequate structure to the        lyophilized cake, e.g., one or more of mannitol, lactose,        sucrose, trehalose, sorbitol, glucose, raffinose, arginine,        glycine, histidine, dextran (e.g., dextran 40),        polyvinylpyrrolidone, polyethylene glycol, and polypropylene        glycol, e.g., one or more of mannitol, glucose, sucrose,        lactose, trehalose, and dextran (e.g., dextran 40).    -   1.15 Kit 1.14 the kit comprises 5 or 10 or 50 mg to 2 or 5 g of        one or more bulking agents, e.g., from about 50 or 100 mg to        200, 300, 500, or 800 mg, or 1, 1.5, 2, 3, 4, or 5 g of one or        more bulking agents.    -   1.16 Kit 1.3-1.15 wherein the kit comprises dextran (e.g.,        dextran 40).    -   1.17 Kit 1.16 wherein the kit comprises 5 or 10 or 50 mg to 2 or        5 g dextran (e.g., dextran 40), e.g., from about 50 or 100 mg to        200, 300, 500, or 800 mg, or 1, 1.5, 2, 3, 4, or 5 g dextran        (e.g., dextran 40).    -   1.18 Kit 1.3-1.17 wherein the composition comprises one or more        solubilizing agents, e.g., ethylenediamine tetraacetic acid        (EDTA) or a slat thereof (e.g., calcium disodium EDTA, disodium        EDTA, sodium EDTA), alpha cyclodextrin,        hydroxypropyl-β-cyclodextrin, polysorbate 80, tert-butanol,        isopropanol, dichloromethane, ethanol, acetone, and glycerol;        one or more collapse temperature modifiers which may shift the        overall collapse temperature higher, e.g., one or more of        dextran, Ficoll®, gelatin, and hydroxyethyl starch; one or more        tonicity modifiers, e.g., one or more of sodium chloride,        potassium chloride, sucrose, mannitol, glucose, and lactose; and        one or more antimicrobial agents, e.g., one or more of benzyl        alcohol, phenol, 2-phenoxyethanol, m-cresol, parabens (e.g.,        methyl paraben, ethyl paraben, propyl paraben), benzalkonium        chloride, benzethonium chloride, myristyl gamma-picolinium salt        (e.g., myristyl gamma-picolinium chloride), and organomercury        compounds and salts (e.g., phenyl mercuric acetate, phenyl        mercuric borate, phenyl mercuric nitrate, and thimerosal).    -   1.19 Kit 1.3-1.18 wherein the compound of Formula I, e.g., the        compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, and the one pharmaceutically        acceptable excipients are in the same container or in one or        more different containers.    -   1.20 Kit 1.19 wherein the kit comprises one or more buffering        agents, e.g., sodium citrate, potassium citrate, sodium        phosphate (e.g., NaH₂PO₄ and/or Na₂HPO₄), potassium phosphate        (e.g., KH₂PO₄ and/or K₂HPO₄), tris(hydroxymethyl)aminomethane        (also known as tris base), tris(hydroxymethyl)aminomethane        acetate (also known as tris acetate), zinc chloride, meglumine,        sodium acetate, potassium acetate, sodium hydroxide, and        arginine, e.g., one or more of sodium citrate, Na₂HPO₄,        tris(hydroxymethyl)aminomethane, and tris acetate, e.g.,        Na₂HPO₄, e.g., tris(hydroxymethyl)aminomethane, e.g.,        tris(hydroxymethyl)aminomethane acetate, wherein the one or more        buffering agents are in the same container as the compound of        Formula I, e.g., the compound of 1.1-1.52, or, e.g., the        compound of Formula II, e.g., the compound of 2.1-2.26, or in        one or more different containers.    -   1.21 Kit 1.20 wherein the compound of Formula I, e.g., the        compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, and one or more of sodium        citrate and sodium phosphate (e.g., Na₂HPO₄) are in the same        container or in one or more different containers.    -   1.22 Kit 1.20 wherein the compound of Formula 1, e.g., the        compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, and sodium citrate are in the        same container or in different containers.    -   1.23 Kit 1.20 wherein the compound of Formula I, e.g., the        compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, and sodium phosphate (e.g.,        Na₂HPO₄) are in the same container or in different containers.    -   1.24 Kit 1.19-1.23 wherein the kit comprises one or more bulking        agents, e.g., one or more of mannitol, lactose, sucrose,        trehalose, sorbitol, glucose, raffinose, arginine, glycine,        histidine, dextran (e.g., dextran 40), polyvinylpyrrolidone,        polyethylene glycol, and polypropylene glycol, e.g., one or more        of mannitol, glucose, sucrose, lactose, trehalose, and dextran        (e.g., dextran 40), wherein the one or more bulking agents are        in the same container as the compound of Formula I, e.g., the        compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, or any other component of the        kit, or in one or more different containers, e.g., in any        combination in any number of different containers.    -   1.25 Kit 1.24 wherein the compound of Formula I, e.g., the        compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, and dextran (e.g., dextran 40)        are in the same container or in different containers.    -   1.26 Kit 1.19-1.25 wherein the kit comprises one or more        solubilizing agents, e.g., ethylenediamine tetraacetic acid        (EDTA) or a salt thereof (e.g., calcium disodium EDTA, disodium        EDTA, sodium EDTA), alpha cyclodextrin,        hydroxypropyl-β-cyclodextrin, polysorbate 80, tert-butanol,        isopropanol, dichloromethane, ethanol, acetone, and glycerol;        one or more collapse temperature modifiers, e.g., one or more of        dextran, Ficoll®, gelatin, and hydroxyethyl starch; one or more        tonicity modifiers, e.g., one or more of sodium chloride,        potassium chloride, sucrose, mannitol, glucose, and lactose; and        one or more antimicrobial agents, e.g., one or more of benzyl        alcohol, phenol, 2-phenoxyethanol, m-cresol, chlorobutanol,        parabens (e.g., methyl paraben, ethyl paraben, and propyl        paraben), benzalkonium chloride, benzethonium chloride, myristyl        gamma-picolinium salt (e.g., myristyl gamma-picolinium        chloride), and organomercury compounds and salts (e.g., phenyl        mercuric acetate, phenyl mercuric borate, phenyl mercuric        nitrate, and thimerosal), wherein the one or more solubilizing        agents, collapse temperature modifiers, tonicity modifiers, and        antimicrobial agents are in the same container as the compound        of Formula I, e.g., the compound of 1.1-1.52, or, e.g., the        compound of Formula II, e.g., the compound of 2.1-2.26, or any        other component of the kit, or in one or more different        containers, e.g., in any combination in any number of different        containers.    -   1.27 Kit I or 1.1-1.26 wherein the compound of Formula I, e.g.,        the compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, is crystalline.    -   1.28 Kit I or 1.1-1.26 wherein the compound of Formula I, e.g.,        the compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, is amorphous.    -   1.29 Kit I or 1.1-1.28 wherein the compound of Formula I, e.g.,        the compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, is lyophilized, e.g., by        freezing, primary drying, and secondary drying.    -   1.30 Kit 1.2-1.29 wherein the compound of Formula I, e.g., the        compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, and the one or more        pharmaceutically acceptable excipients are lyophilized.    -   1.31 Kit I or 1.1-1.30 wherein the compound of Formula 1, e.g.,        the compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, is suitable for constitution, or        reconstitution if lyophilized, with a solvent into a        pharmaceutically acceptable liquid (e.g., a solution or        suspension, e.g., a solution).    -   1.32 Kit I or 1.1-1.31 wherein the kit comprises a solvent,        e.g., a sterile solution, e.g., sterile water for injection, a        sterile solution comprising dextrose (e.g., dextrose injection        5%), a sterile solution comprising sodium chloride (e.g., 0.9%        sodium chloride injection), a sterile solution comprising benzyl        alcohol (e.g., bacteriostatic water for injection with benzyl        alcohol or bacteriostatic sodium chloride for injection with        benzyl alcohol), or Lactated Ringer's.    -   1.33 Kit I or 1.1-1.32 wherein the kit comprises 0.5 to 500 mL        solvent, e.g., from about 1 to 2 or 500 mL, e.g., from about 1        or 2 to 5, 10, 25, 50, 75, 100, 150, 200, 300 or 500 mL, e.g.,        from about 1 or 2 to 5, 10, 25, 50, 75, 100, or 200 mL, e.g.,        from about 5 to 10, 25, 50, or 100 mL.    -   1.34 Kit I or 1.1-1.33 wherein the kit comprises 0.5 to 500 mL        sterile solution, e.g., sterile water for injection, a sterile        solution comprising dextrose (e.g., dextrose injection 5%), a        sterile solution comprising sodium chloride (e.g., 0.9% sodium        chloride injection), a sterile solution comprising benzyl        alcohol (e.g., bacteriostatic water for injection with benzyl        alcohol or bacteriostatic sodium chloride for injection with        benzyl alcohol), or Lactated Ringer's, e.g., from about 1 or 2        mL to 500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 50, 75,        100, 150, 200, 300 or 500 mL, e.g., from about 1 or 2 mL to 5,        10, 25, 50, 75, 100, or 200 mL, e.g., from about 5 to 10, 25,        50, or 100 mL.    -   1.35 Kit I or 1.1-1.34 wherein the kit comprises sterile water        for injection or a sterile solution comprising sodium chloride        (e.g., 0.9% sodium chloride injection).    -   1.36 Kit 1.35 wherein the kit comprises 0.5 to 500 mL sterile        water for injection, e.g., from about 1 or 2 mL to 500 mL, e.g.,        from about 1 or 2 mL to 5, 10, 25, 50, 75, 100, 150, 200, 300 or        500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 50, 75, 100, or        200 mL, e.g., from about 5 to 10, 25, 50, or 100 mL.    -   1.37 Kit I or 1.1-1.36 wherein the kit comprises sterile        solution comprising sodium chloride (e.g., 0.9% sodium chloride        injection).    -   1.38 Kit 1.37 wherein the kit comprises 0.5 to 500 mL of a        sterile solution comprising sodium chloride (e.g., 0.9% sodium        chloride injection), e.g., from about 1 or 2 mL to 500 mL, e.g.,        from about 1 or 2 mL to 5, 10, 25, 50, 75, 100, 150, 200, 300 or        500 mL, e.g., from about 1 or 2 mL to 5, 10, 25, 50, 75, 100, or        200 mL, e.g., from about 5 to 10, 25, 50, or 100 mL.    -   1.39 Kit 1.31-1.38 wherein the solvent, e.g., the sterile        solution, comprises a buffering agent, e.g., one or more of        sodium citrate, potassium citrate, sodium phosphate (e.g.,        NaH₂PO₄ and/or Na₂HPO₄), potassium phosphate (e.g., KH₂PO₄        and/or K₂HPO₄), tris(hydroxymethyl)aminomethane (also known as        tris base), tris(hydroxymethyl)aminomethane acetate (also known        as tris acetate), zinc chloride, meglumine, sodium acetate,        potassium acetate, sodium hydroxide, and arginine, e.g., one or        more of sodium citrate, Na₂HPO₄,        tris(hydroxymethyl)aminomethane, and        tris(hydroxymethyl)aminomethane acetate, e.g., Na₂HPO₄, e.g.,        tris(hydroxymethyl)aminomethane, e.g.,        tris(hydroxymethyl)aminomethane acetate.    -   1.40 Kit 1.39 wherein the solvent, e.g., the sterile solution,        comprises 1 or 5 mg to 200 or 500 mg of one or more buffering        agents, e.g., from about 1 or 5 or 10 mg to 50, 100, 150, 200,        250, 300, 350, 400, 450, or 500 mg.    -   1.41 Kit 1.39 or 1.40 wherein the solvent, e.g. the sterile        solution, comprises one or more of sodium citrate and sodium        phosphate, e.g., Na₂HPO₄.    -   1.42 Kit 1.39-1.41 wherein the solvent, e.g. the sterile        solution, comprises sodium citrate.    -   1.43 Kit 1.42 wherein the solvent, e.g., the sterile solution,        comprises 1 or 5 mg to 200 or 500 mg sodium citrate, e.g., from        about 1 or 5 or 10 mg to 50, 100, 150, 200, 250, 300, 350, 400,        450, or 500 mg sodium citrate.    -   1.44 Kit 1.39-1.43 wherein the solvent, e.g., the sterile        solution, comprises sodium phosphate, e.g., Na₂HPO₄.    -   1.45 Kit 1.44 wherein the solvent, e.g., the sterile solution,        comprises 1 or 5 mg to 200 or 500 mg sodium phosphate, e.g.,        from about 1 or 5 or 10 mg to 50, 100, 150, 200, 250, 300, 350,        400, 450, or 500 mg sodium phosphate, e.g., Na₂HPO₄.    -   1.46 Kit 1.32-1.45 wherein the solvent, e.g., the sterile        solution, comprises one or more bulking agents, e.g., one or        more of maltose, mannose, ribose, cyclodextrin, mannitol,        lactose, sucrose, trehalose, sorbitol, glucose, raffinose,        arginine, glycine, histidine, dextran (e.g., dextran 40),        polyvinylpyrrolidone, polyethylene glycol, and polypropylene        glycol, e.g., one or more of mannitol, glucose, sucrose,        lactose, trehalose, and dextran (e.g., dextran 40).    -   1.47 Kit 1.32-1.46 wherein the solvent, e.g., the sterile        solution, comprises 5 or 10 or 50 mg to 2 or 5 g of one or more        bulking agents, e.g., from about 50 or 100 mg to 200, 300, 500,        or 800 mg, or 1, 1.5, 2, 3, 4, or 5 g of one or more bulking        agents.    -   1.48 Kit 1.32-1.47 wherein the solvent, e.g., the sterile        solution, comprises dextran (e.g., dextran 40).    -   1.49 Kit 1.48 wherein the solvent, e.g. the sterile solution,        comprises 5 or 10 or 50 mg to 2 or 5 g dextran (e.g., dextran        40), e.g., from about 50 or 100 mg to 200, 300, 500, or 800 mg,        or 1, 1.5, 2, 3, 4, or 5 g dextran (e.g., dextran 40).    -   1.50 Kit 1.32-1.49 wherein the solvent, e.g., the sterile        solution, comprises one or more solubilizing agents, e.g.,        ethylenediamine tetraacetic acid (EDTA) or a salt thereof (e.g.,        calcium disodium EDTA, disodium EDTA, sodium EDTA), alpha        cyclodextrin, hydroxypropyl-β-cyclodextrin, polysorbate 80,        tert-butanol, isopropanol, dichloromethane, ethanol, acetone,        and glycerol; one or more collapse temperature modifiers which        may shift the overall collapse temperature higher, e.g., one or        more of dextran, Ficoll®, gelatin, and hydroxyethyl starch; one        or more tonicity modifiers, e.g., one or more of sodium        chloride, potassium chloride, sucrose, mannitol, and glucose;        and one or more antimicrobial agents, e.g., one or more of        benzyl alcohol, phenol, 2-phenoxyethanol, m-cresol,        chlorobutanol, parabens (e.g., methyl paraben, ethyl paraben,        propyl paraben), benzalkonium chloride, benzethonium chloride,        myristyl gamma-picolinium salt (e.g., myristyl gamma-picolinium        chloride), and organomercury compounds and salts (e.g., phenyl        mercuric acetate, phenyl mercuric borate, phenyl mercuric        nitrate, and thimerosal).    -   1.51 Kit 1.32-1.50 wherein the compound of Formula I, e.g., the        compound of 1.1-1.52, or, e.g., the compound of Formula II,        e.g., the compound of 2.1-2.26, is admixed with the solvent to        form a solution wherein the pH is between pH 7 and pH 10.5,        e.g., between pH 7 and pH 9.5, e.g., between pH 7 and pH 8.    -   1.52 Kit 1.51 wherein the solution is filtered to remove        particles and microbes, e.g., filtered prior to injection.    -   1.53 Kit 1.51 or 1.52 wherein the solution is administered about        24 hours, 12 hours, 10 hours, 8 hours, 2 hours, 1 hour, 30        minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 3        minutes, 2 minutes or 1 minute or less after admixture.    -   1.54 Kit I or 1.1-1.53 wherein the kit comprises one or more        additional therapeutic agents, e.g., one or more additional        therapeutic agents for cerebral edema, stroke, traumatic brain        injury, glioma (e.g., glioblastoma), meningitis, acute mountain        sickness, infection, metabolic disorder, hypoxia, water        intoxication, hepatic failure, hepatic encephalopathy, diabetic        ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob disease,        lupus cerebritis, optic nerve edema, hyponatremia, fluid        retention, ovarian hyperstimulation syndrome, epilepsy, retinal        ischemia or other diseases of the eye associated with        abnormalities in intraocular pressure and/or tissue hydration,        myocardial ischemia, myocardial ischemia/reperfusion injury,        myocardial infarction, myocardial hypoxia, congestive heart        failure, sepsis, neuromyelitis optica, or migraines.    -   1.55 Kit I or 1.1-1.128 wherein the kit comprises one or more        additional therapeutic agents, e.g., one or more additional        therapeutic agents for pulmonary edema, fibromyalgia, or        multiple sclerosis.    -   1.56 Kit I or 1.1-1.55 wherein the kit comprises instructions        for using the compound of Formula 1, e.g., the compound of        1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, to treat or control a disease or condition        mediated by an aquaporin, e.g., diseases or conditions of water        imbalance and other diseases, for example, edema of the brain or        spinal cord, e.g., cerebral edema, e.g. cerebral edema        consequent to head trauma, ischemic stroke, glioma, meningitis,        acute mountain sickness, epileptic seizure, infection, metabolic        disorder, hypoxia (including general systemic hypoxia and        hypoxia due to cardiac arrest), water intoxication, hepatic        failure, hepatic encephalopathy, diabetic ketoacidosis, abscess,        eclampsia, Creutzfeldt-Jakob disease, lupus cerebritis, cardiac        arrest, microgravity and/or radiation exposure, or an invasive        central nervous system procedure, e.g., neurosurgery,        endovascular clot removal, spinal tap, aneurysm repair, or deep        brain stimulation or, e.g., spinal cord edema consequent to        spinal cord trauma, e.g., spinal cord compression; or optic        nerve edema, e.g., optic nerve edema consequent to microgravity        and/or radiation exposure; or retinal edema; or hyponatremia or        excessive fluid retention, e.g., consequent to heart failure        (HF), liver cirrhosis, nephrotic disorder, syndrome of        inappropriate antidiuretic hormone secretion (SIADH), or        infertility treatment; or ovarian hyperstimulation syndrome; or        epilepsy, retinal ischemia or other diseases of the eye        associated with abnormalities in intraocular pressure and/or        tissue hydration, myocardial ischemia, myocardial        ischemia/reperfusion injury, myocardial infarction, myocardial        hypoxia, congestive heart failure, sepsis, neuromyelitis optica,        or glioblastoma; or migraines.    -   1.57 Kit I or 1.1-1.56 wherein the kit comprises instructions        for using        2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl        dihydrogen phosphate to treat or control a disease or condition        mediated by an aquaporin, e.g., diseases or conditions of water        imbalance and other diseases, for example, pulmonary edema,        fibromyalgia, or multiple sclerosis.    -   1.58 Kit I or 1.1-1.57 wherein the kit comprises instructions        for administering the compound of Formula I, e.g., the compound        of 1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, to a patient in need thereof.    -   1.59 Kit I or 1.1-1.57 wherein the kit comprises instructions        for mixing the compound of Formula I, e.g., the compound of        1.1-1.52, or, e.g., the compound of Formula II, e.g., the        compound of 2.1-2.26, and one or more pharmaceutically        acceptable excipients.    -   1.60 Kit I wherein the kit comprises a pharmaceutical        composition comprising a compound of Formula I, e.g., a compound        of 1.1-1.52, or, e.g., a compound of Formula II, e.g., a        compound of 2.1-2.26, e.g., Composition I, e.g., a composition        of 1.1-1.57.    -   1.61 Kit 1.60 wherein the kit comprises instructions for using        the pharmaceutical composition to treat or control a disease or        condition mediated by an aquaporin, e.g., diseases or conditions        of water imbalance and other diseases, for example, edema of the        brain or spinal cord, e.g., cerebral edema, e.g. cerebral edema        consequent to head trauma, ischemic stroke, glioma, meningitis,        acute mountain sickness, epileptic seizure, infection, metabolic        disorder, hypoxia (including general systemic hypoxia and        hypoxia due to cardiac arrest), water intoxication, hepatic        failure, hepatic encephalopathy, diabetic ketoacidosis, abscess,        eclampsia, Creutzfeldt-Jakob disease, lupus cerebritis, cardiac        arrest, microgravity and/or radiation exposure, or an invasive        central nervous system procedure, e.g., neurosurgery,        endovascular clot removal, spinal tap, aneurysm repair, or deep        brain stimulation or, e.g., spinal cord edema consequent to        spinal cord trauma, e.g., spinal cord compression; or optic        nerve edema, e.g., optic nerve edema consequent to microgravity        and/or radiation exposure; or retinal edema; or hyponatremia or        excessive fluid retention, e.g., consequent to heart failure        (HF), liver cirrhosis, nephrotic disorder, syndrome of        inappropriate antidiuretic hormone secretion (SIADH), or        infertility treatment; or ovarian hyperstimulation syndrome; or        epilepsy, retinal ischemia or other diseases of the eye        associated with abnormalities in intraocular pressure and/or        tissue hydration, myocardial ischemia, myocardial        ischemia/reperfusion injury, myocardial infarction, myocardial        hypoxia, congestive heart failure, sepsis, neuromyelitis optica,        or glioblastoma; or migraines.    -   1.62 Kit 1.60 wherein the kit comprises instructions for using        the pharmaceutical composition to treat or control a disease or        condition mediated by an aquaporin, e.g., diseases or conditions        of water imbalance and other diseases, for example, pulmonary        edema, fibromyalgia, or multiple sclerosis.    -   1.63 Kit 1.60 wherein the kit comprises instructions for        administering the pharmaceutical composition to a patient in        need thereof.    -   1.64 Kit 1.60 wherein the kit comprises instructions for        preparing the pharmaceutical composition.    -   1.65 Kit I or 1.1-1.64 wherein the kit is for use in any of the        methods described herein, e.g., for use in Method A, e.g.,        Method A.1-A.58, for use in Method B, e.g., Method B.1-B.41,        e.g., for use in Method C, e.g., C.1-C.8, e.g., for use in        Method D, e.g., D.1-D.19, e.g., for use in Method E, e.g.,        E.1-E.5, e.g., for use in Method F, e.g., F.1-F.5, e.g., for use        in Method G, e.g., G.1-G.58.

In some embodiments, the kit is prepared by transferring a liquidcomprising a compound of Formula I, e.g., a compound of 1.1-1.52, or,e.g., the compound of Formula II, e.g., the compound of 2.1-2.26, to acontainer, e.g., a vial, in a predetermined volume first and thensubjecting the liquid to a lyophilization process. Alternatively, liquidcan be lyophilized in a large volume and then a predetermined amount ofthe lyophilized preparation can be placed in a container.

In yet another embodiment, provided is a compound of Formula III

wherein:R³⁰, R³¹, R³², R³³, and R³⁴ are independently H, halogen (e.g., Cl orBr), C₁₋₄-alkyl, C₁₋₄-haloalkyl (e.g., —CF₃), or cyano; andR³⁵ and R³⁶ are independently protecting groups, e.g., wherein R³⁵ andR³⁶ are independently a protecting group comprising Si, S, N, and/or O,e.g., wherein R³⁵ and R³⁶ are independently a protecting groupcomprising an optionally substituted cyclic or acyclic ether, anoptionally substituted silyl (e.g., —Si(C₁₋₆-alkyl)₃, e.g.,—Si(C₁₋₄-alkyl)₃, e.g., —Si(CH₃)₃), an optionally substituted silylether, an optionally substituted ester, an optionally substitutedketone, or an optionally substituted thioether, e.g., wherein R³⁵ andR³⁶ are independently —CH₂OR′, —CH₂SR′,

—C(OC₁₋₆-alkyl)(R′)₂, —CH(R′)OR′, —C(R′)₃, —Si(R″)₃, —C(O)R″, or—C(O)OR″, wherein each R′ is independently H, C₁₋₆-alkyl (e.g.,C₁₋₄-alkyl), —CH₂Si(R″)₃, —CH₂-Aryl (e.g., phenyl), —C₁₋₆-alkenyl,—CH₂OSi(R″)₃, alkoxyalkyl, or —CH₂CH₂Si(R″)₃ and each R″ isindependently C₁₋₆-alkyl (e.g., C₁₋₄-alkyl) or aryl optionallysubstituted with alkoxy (e.g., —C₁₋₆-alkoxy, e.g., —C₁₋₄-alkoxy),halogen, cyano, or aryl (e.g., phenyl), wherein each R¹ is optionallysubstituted with alkyl, alkoxyalkyl, or aryl, e.g.,—(CH₂CH₂)_(n)—Si(R³⁷)₃), wherein each R³⁷ is independently C₁₋₆-alkyl,e.g., C₁₋₄-alkyl and n is 0 or 1,and wherein R³⁵ and R³⁶ are not both —CH₂—C₆H₅.

Further provided is a compound of Formula III as follows:

-   -   3.1 Formula III wherein R³⁰, R³¹, R³², R³³, and R³⁴ are        independently selected from H, halogen (e.g., Cl or Br),        C₁₋₄-haloalkyl (e.g., —CF₃), and cyano.    -   3.2 Formula III or 3.1 wherein R³⁰, R³¹, R³², R³³, and R³⁴ are        independently selected from H, halogen (e.g., Cl or Br), and        C₁₋₄-haloalkyl (e.g., —CF₃).    -   3.3 Formula III, 3.1, or 3.2 wherein R³⁰, R³², and R³⁴ are        independently selected from halogen (e.g., Cl or Br) and        C₁₋₄-haloalkyl (e.g., —CF₃) and R³¹ and R³³ are H.    -   3.4 Formula III or 3.1-3.3 wherein R³⁰, R³², and R³⁴ are        independently halogen (e.g., Cl or Br) and R³¹ and R³³ are H.    -   3.5 Formula III or 3.1-3.4 wherein R³⁰, R³², and R³⁴ are Cl and        R³¹ and R³³ are H.    -   3.6 Formula III or 3.1-3.3 wherein R³⁰, R³², and R³⁴ are        independently C₁₋₄-haloalkyl (e.g., —CF₃) and R³¹ and R³³ are H.    -   3.7 Formula III, 3.1-3.3, or 3.6 wherein R³⁰, R³², and R³⁴ are        —CF₃.    -   3.8 Formula III or 3.1-3.3 wherein R³⁰, R³², and R³⁴ are        independently F, Cl, Br, or —CF₃ and R³¹ and R³³ are H.    -   3.9 Formula III or 3.1-3.3 wherein R³⁰ is halogen (e.g., Cl or        Br), R³¹ and R³³ are H, and R³² and R³⁴ are independently        C₁₋₄-haloalkyl (e.g., —CF₃).    -   3.10 Formula 3.8 or 3.9 wherein R³⁰ is Cl or Br and R³² and R³⁴        are —CF₃.    -   3.11 Formula 3.10 wherein R³⁰ is Cl.    -   3.12 Formula 3.10 wherein R³⁰ is Br.    -   3.13 Formula III or 3.1 wherein R³⁰, R³¹, R³², R³³, and R³⁴ are        independently H, halogen (e.g., Cl or Br), or cyano.    -   3.14 Formula 3.13 wherein R³⁰ and R³¹ are independently halogen        (e.g., Cl or Br), R³² and R³⁴ are H, and R³³ is cyano.    -   3.15 Formula 3.14 wherein R³⁰ and R³¹ are Cl.    -   3.16 Formula III or 3.1-3.15 wherein R³⁵ and R³⁶ are        independently selected from a protecting group comprising Si.    -   3.17 Formula III or 3.1-3.15 wherein R³⁵ and R³⁶ are        independently selected from —(CH₂CH₂)_(n)—Si(R³⁷)₃, wherein each        R³⁷ is independently C₁₋₆-alkyl, e.g., C₁₋₄-alkyl, e.g., —CH₃,        and n is 0 or 1, e.g., 0, e.g., 1.    -   3.18 Formula 3.17 wherein n is 1.    -   3.19 Formula III or 3.1-3.18 wherein R³⁵ and R³⁶ are the same.    -   3.20 Formula III or 3.1-3.19 wherein R³⁵ and R³⁶ are        —CH₂—CH₂—Si(CH₃)₃.    -   3.21 Formula III wherein the compound is

In yet another embodiment, provided is a compound of Formula XX

wherein:R⁴⁰ and R⁴¹ are independently protecting groups, e.g., wherein R⁴⁰ andR⁴¹ are independently a protecting group comprising Si, S, N, and/or O,e.g., wherein R⁴⁰ and R⁴¹ are independently a protecting groupcomprising an optionally substituted cyclic or acyclic ether, anoptionally substituted silyl (e.g., —Si(C₁₋₆-alkyl)₃, e.g.,—Si(C₁₋₄-alkyl)₃, e.g., —Si(CH₃)₃), an optionally substituted silylether, an optionally substituted ester, an optionally substitutedketone, or an optionally substituted thioether, e.g., wherein R⁴⁰ andR⁴¹ are independently —CH₂OR′, —CH₂SR′,

—C(OC₁₋₆-alkyl)(R′)₂, —CH(R′)OR′, —C(R′)₃, —Si(R″)₃, —C(O)R″, or—C(O)OR″, wherein each R′ is independently H, C₁₋₆-alkyl (e.g.,C₁₋₄-alkyl), —CH₂Si(R″)₃, —CH₂-Aryl (e.g., phenyl), —C₁₋₆-alkenyl,—CH₂OSi(R″)₃, alkoxyalkyl, or —CH₂CH₂Si(R″)₃ and each R″ isindependently C₁₋₆-alkyl (e.g., C₁₋₄-alkyl) or aryl optionallysubstituted with alkoxy (e.g., —C₁₋₆-alkoxy, e.g., —C₁₋₄-alkoxy),halogen, cyano, or aryl (e.g., phenyl), wherein each R¹ is optionallysubstituted with alkyl, alkoxyalkyl, or aryl, e.g.,—(CH₂CH₂)_(n)—Si(R³⁷)₃), wherein each R³⁷ is independently C₁₋₆-alkyl,e.g., C₁₋₄-alkyl and n is 0 or 1,and wherein R⁴¹ and R³⁴¹ are not both —CH₂—C₆H₅.

Further provided is a compound of Formula XX as follows:

-   -   20.1 Formula XX wherein R⁴⁰ and R⁴¹ are independently selected        from a protecting group comprising Si.    -   20.2 Formula XX or 20.1, wherein R⁴⁰ and R⁴¹ are independently        selected from —(CH₂CH₂)_(n)—Si(R³⁷)₃, wherein each R³⁷ is        independently C₁₋₄-alkyl, e.g., —CH₃, and n is 0 or 1.    -   20.3 Formula XX, 20.1, or 20.2, wherein is 1.    -   20.4 Formula XX or 20.1-20.3, wherein R⁴⁰ and R⁴¹ are the same.    -   20.5 Formula XX or 20.1-20.4 wherein each R³⁷ is —CH₃.    -   20.6 Formula XX or 320.1-20.5 wherein R³⁵ and R³⁶ are        —CH₂—CH₂—Si(CH₃)₃.

Compounds of Formula I, e.g., compounds of 1.1-1.52, or, e.g., compoundsof Formula II, e.g., compounds of 2.1-2.26, compounds Formula III, e.g.,compounds of 3.1-3.21, or compounds of Formula XX, e.g., 20.1-20.5,include their polymorphs, hydrates, solvates and complexes.

Some individual compounds within the scope of this disclosure maycontain double bonds. Representations of double bonds herein are meantto include both the E and the Z isomer of the double bond. In addition,some compounds within the scope of this disclosure may contain one ormore asymmetric centers. This disclosure includes the use of any of theoptically pure stereoisomers as well as any combination ofstereoisomers.

It is also intended that compounds of Formula I, e.g., compounds offormula 1.1-1.52, or, e.g., compounds of Formula II, e.g., compounds offormula 2.1-2.26, and compounds Formula III, e.g., compounds of formula3.1-3.21, encompass their stable and unstable isotopes. Stable isotopesare nonradioactive isotopes which contain one additional neutroncompared to the abundant nuclides of the same species (i.e., element).It is expected that the activity of compounds comprising such isotopeswould be retained, and such compound would also have utility formeasuring pharmacokinetics of the non-isotopic analogs. For example, thehydrogen atom at a certain position on a compound of Formula I, e.g., acompound of 1.1-1.52, or, e.g., a compound of Formula II, e.g., acompound of 2.1-2.26, or a compound of Formula III, e.g., a compound offormula 3.1-3.21, may be replaced with deuterium (a stable isotope whichis non-radioactive). Examples of known stable isotopes include, but notlimited to, deuterium, ¹³C, ¹⁵N, ¹⁸O. Alternatively, unstable isotopes,which are radioactive isotopes which contain additional neutronscompared to the abundant nuclides of the same species (i.e., element),e.g., ¹²³I, ¹³¹I, ¹²⁵I, ¹¹C, ¹⁸F, may replace the corresponding abundantspecies of, C, and F. Another example of a useful isotope of a compoundof Formula I, e.g., a compound of 1.1-1.52, or, e.g., a compound ofFormula II, e.g., a compound of 2.1-2.26, or a compound of Formula III,e.g., a compound of formula 3.1-3.21, is the ¹¹C isotope. These radioisotopes may be useful for radio-imaging and/or pharmacokinetic studiesof compounds of Formula I, e.g., compounds of 1.1-1.52, or, e.g.,compounds of Formula II, e.g., compounds of 2.1-2.26.

Compounds of Formula I, e.g., compounds of formula 1.1-1.52, or, e.g.,compounds of Formula II, e.g., compounds of formula 2.1-2.26, andcompounds of Formula III, e.g., 3.1-3.21, may be made using the methodsas described and exemplified herein and by methods similar thereto andby methods known in the chemical art. Such methods include, but notlimited to, those described below. If not commercially available,starting materials for these processes may be made by procedures whichare selected from the chemical art using techniques which are similar oranalogous to the synthesis of known compounds.

In yet another embodiment, provided are novel processes for thesynthesis compounds of Formula I, e.g., compounds of formula 1.1-1.52,or, e.g., compounds of Formula II, e.g., compounds of formula 2.1-2.26.Novel intermediates of Formula III, e.g., compounds of formula 3.1-3.21,may be used in the synthesis of compounds of Formula I, e.g., compoundsof formula 1.1-1.52 and in the synthesis of compounds of Formula II,e.g., compounds of formula 2.1-2.26.

U.S. Pat. No. 7,626,042 reports a process for preparing2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogenphosphate from Compound No. 50:

U.S. Pat. No. 7,626,042 describes that palladium hydroxide on carbon wasadded to Compound No. 50 in ethyl acetate and the mixture was stirred atroom temperature for 1 hour under hydrogen atmosphere.

The inventors have found the process described in U.S. Pat. No.7,626,042 results in dechlorination of Compound No. 50, which results ina contaminant that is difficult to remove.

Thus, in yet another embodiment, provided is a process (Process I) forsynthesizing a compound of Formula I, e.g., a compound of formula1.1-1.52, comprising deprotonating a compound of Formula IV

with Q or a salt thereof (e.g., NaOH or KOH), wherein R¹, R², R³, R⁴,R⁵, and Q are as defined for Formula I.

Further provided is Process I as follows:

-   -   1.1 Process I wherein R¹, R², R³, R⁴, and R⁵ are independently        H, halogen (e.g., Cl or Br), C₁₋₄-haloalkyl (e.g., —CF₃), or        cyano.    -   1.2 Process I or 1.1 wherein R¹, R², R³, R⁴, and R⁵ are        independently H, halogen (e.g., Cl or Br), or C₁₋₄-haloalkyl        (e.g., —CF₃).    -   1.3 Process I, 1.1, or 1.2 wherein R¹, R³, and R⁵ are        independently halogen (e.g., Cl or Br) or C₁₋₄-haloalkyl (e.g.,        —CF₃) and R² and R⁴ are H.    -   1.4 Process I or 1.1-1.3 wherein R¹, R³, and R⁵ are        independently halogen (e.g., Cl or Br) and R² and R⁴ are H.    -   1.5 Process I or 1.1-1.4 wherein R¹, R³, and R⁵ are Cl and R²        and R⁴ are H.    -   1.6 Process I or 1.1-1.3 wherein R¹, R³, and R⁵ are        independently C₁₋₄-haloalkyl (e.g., —CF₃) and R² and R⁴ are H.    -   1.7 Process 1.6 wherein R¹, R³, and R⁵ are —CF₃.    -   1.8 Process I or 1.1-1.3 wherein R¹, R³, and R⁵ are        independently F, Cl, Br, or —CF₃ and R² and R⁴ are H.    -   1.9 Process I or 1.1-1.3 wherein R¹ is halogen (e.g., Cl or Br),        R² and R⁴ are H, and R³ and R⁵ are independently C₁₋₄-haloalkyl        (e.g., —CF₃).    -   1.10 Process 1.8 or 1.9 wherein R¹ is Cl or Br and R³ and R⁵ are        —CF₃.    -   1.11 Process 1.10 wherein R¹ is Cl.    -   1.12 Process 1.10 wherein R¹ is Br.    -   1.13 Process I or 1.1 wherein R¹, R², R³, R⁴, and R⁵ are        independently H, halogen (e.g., Cl or Br), or cyano.    -   1.14 Process 1.13 wherein R¹ and R² are independently halogen        (e.g., Cl or Br), R³ and R⁵ are H, and R⁴ is cyano.    -   1.15 Process 1.14 wherein R¹ and R² are Cl.    -   1.16 Process I or 1.1-1.15 wherein Q comprises N, e.g., Q is        HOR⁸NH₂, (HOR⁸)₂NH, or (HOR⁸)₃N.    -   1.17 Process I or 1.1-1.14 wherein Q is HOR⁸NH₂.    -   1.18 Process I or 1.1-1.14 wherein Q is (HOR⁸)₂NH.    -   1.19 Process I or 1.1-1.14 wherein Q is (HOR⁸)₃N.    -   1.20 Process I or 1.1-1.19 wherein R⁸ is —CH₂—CH₂—.    -   1.21 Process I or 1.1-1.15 wherein Q is a salt.    -   1.22 Process 1.21 wherein Q comprises sodium (e.g., NaOH,        NaHCO₃, Na₂CO₃, NaOMe, NaOEt, or NaH).    -   1.23 Process 1.22 wherein Q is NaOH.    -   1.24 Process 1.21 wherein Q comprises potassium (e.g., KOH,        KHCO₃, K₂CO₃, KOMe, KOEt, or KH).    -   1.25 Process 1.24 wherein Q is KOH.    -   1.26 Process I wherein R¹ is halogen (e.g., Cl or Br), R² and R⁴        are H, and R³ and R⁵ are independently C₁₋₄-haloalkyl (e.g.,        —CF₃).    -   1.27 Process 1.26 wherein R¹ is Cl or Br and R³ and R⁵ are —CF₃.    -   1.28 Process 1.27 wherein R¹ is Cl.    -   1.29 Process 1.26-1.28 wherein Q is HOR⁸NH₂.    -   1.30 Process 1.29 wherein R⁸ is —CH₂—CH₂—.    -   1.31 Process 1.26-1.28 wherein Q is (HOR⁸)₂NH.    -   1.32 Process 1.31 wherein R⁸ is —CH₂—CH₂—.    -   1.33 Process 1.26-1.28 wherein Q is (HOR⁸)₃N.    -   1.34 Process 1.33 wherein R⁸ is —CH₂—CH₂—.    -   1.35 Process 1.26-1.28 wherein Q comprises sodium (e.g., NaOH,        NaHCO₃, Na₂CO₃, NaOMe, NaOEt, NaH).    -   1.36 Process 1.35 wherein Q is NaOH.    -   1.37 Process 1.26-1.28 wherein Q comprises potassium (e.g., KOH,        KHCO₃, K₂CO₃, KOMe, KOEt, KH).    -   1.38 Process 1.37 wherein Q is KOH.    -   1.39 Process I wherein the compound of Formula IV is:

-   -   1.40 Process 1.39 wherein Q is HOR⁸NH₂, (HOR⁸)₂NH, or (HOR⁸)₃N.    -   1.41 Process 1.40 wherein Q is HOR⁸NH₂.    -   1.42 Process 1.41 wherein R⁸ is —CH₂—CH₂—.    -   1.43 Process 1.40 wherein Q is (HOR⁸)₂NH.    -   1.44 Process 1.43 wherein R⁸ is —CH₂—CH₂—.    -   1.45 Process 1.40 wherein Q is (HOR⁸)₃N.    -   1.46 Process 1.45 wherein R⁸ is —CH₂—CH₂—.    -   1.47 Process 1.39 wherein Q is a salt.    -   1.48 Process 1.47 wherein Q comprises sodium (e.g., NaOH,        NaHCO₃, Na₂CO₃, NaOMc, NaOEt, NaH).    -   1.49 Process 1.48 wherein Q is NaOH.    -   1.50 Process 1.47 wherein Q comprises potassium (e.g., KOH,        KHCO₃, K₂CO₃, KOMe, KOEt, KH).    -   1.51 Process 1.50 wherein Q is KOH.    -   1.52 Process I or 1.1-1.51 wherein the reaction occurs in a        solvent selected from one or more of H₂O and an alcohol (e.g.,        methanol, ethanol, isopropanol).    -   1.53 Process 1.52 wherein the solvent is H₂O.    -   1.54 Process 1.52 wherein the solvent is methanol.    -   1.55 Process I or 1.1-1.54 wherein the reaction is stirred at        room temperature.    -   1.56 Process I or 1.1-1.55 wherein the reaction is stirred for        about 2 hours.    -   1.57 Process I or 1.1-1.56 wherein the compound of Formula IV is        mono-deprotonated.    -   1.58 Process I or 1.1-1.56 wherein the compound of Formula IV is        di-deprotonated    -   1.59 Process I or 1.1-1.58 further comprising deprotecting a        compound of Formula III

-   -   -   wherein R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, and R³⁶ are as defined            above, e.g., a compound of Formula III, e.g., a compound of            formula 3.1-3.21, to form a compound of Formula IV.

    -   1.60 Process 1.59 wherein the compound of Formula III is

-   -   -   wherein R³⁵ and R³⁶ are as defined above, e.g., a compound            of Formula III, e.g., a compound of formula 3.1-3.21.

    -   1.61 Process 1.59 or 1.60 wherein the compound of Formula III is

-   -   1.62 Process 1.59-1.62 wherein the compound of Formula III is        deprotected with a deprotecting agent comprising F.    -   1.63 Process 1.62 wherein the deprotecting agent is        tetra-n-butylammonium fluoride, MgBr₂-diethylether, or BBr3.    -   1.64 Process 1.59-1.62 wherein the deprotecting agent is an        acid.    -   1.65 Process 1.64 wherein the acid is CF₃COOH (also known as TFA        and trifluoroacetic acid).    -   1.66 Process 1.59-1.65 wherein the deprotection reaction is        stirred at room temperature.    -   1.67 Process 1.59-1.66 wherein the deprotection reaction is        stirred for about 2 hours.    -   1.68 Process I or 1.1-1.67 further comprising reacting a        compound of Formula V

-   -   -   with a compound of Formula VI

-   -   -   to form a compound of Formula III, wherein R³⁰, R³¹, R³²,            R³³, R³⁴, R³⁵, and R³⁶ are as defined above for the compound            of Formula III, e.g., the compound of formula 3.1-3.21,            e.g., wherein the compound of Formula VI is a compound of            Formula XX, e.g., 20.1-20.5.

    -   1.69 Process 1.68 wherein the compound of Formula V is reacted        with a compound of Formula XX, e.g., 20.1-20.5.

    -   1.70 Process 1.68 or 1.69 wherein the compound of Formula V is        reacted with

-   -   1.71 Process 1.68-1.70 wherein the reaction occurs in the        presence of a base.    -   1.72 Process 1.71 wherein the base comprises nitrogen.    -   1.73 Process 1.72 wherein the base is a trialkylamine (e.g.,        (C₁₋₄-alkyl)₃N).    -   1.74 Process 1.73 wherein the base is N,N-diisopropylethylamine        (also known as Hünig's base).    -   1.75 Process 1.68-1.74 wherein the reaction occurs in the        presence of a catalyst.    -   1.76 Process 1.75 wherein the catalyst comprises nitrogen.    -   1.77 Process 1.76 wherein the catalyst is        4-dimethylaminopyridine (also known as DMAP),        1,8-diazabicyclo[5.4.0]undec-7-ene (also known as DBU), or        1,5-diazabicyclo[4.3.0]non-5-ene (also known as DBN).    -   1.78 Process 1.68-1.77 wherein the reaction occurs in CH₃CN and        CCl₄.    -   1.79 Process 1.68-1.78 wherein the reaction is allowed to warm        from about 0° C. to room temperature.    -   1.80 Process 1.68-1.79 wherein the reaction is stirred for about        20 hours.    -   1.81 Process I or 1.1-1.80 further comprising reacting a        compound of Formula VII

-   -   -   to form a compound of Formula V, wherein R³⁰ is defined            above for the compound of Formula III, e.g., the compound of            formula 3.1-3.21.

    -   1.82 Process 1.81 wherein the compound of Formula VII is reacted        with a compound of Formula VIII

-   -   -   wherein R³¹, R³², R³³, and R³⁴ are as defined above for the            compound of Formula III, e.g., 3.1-3.21.

    -   1.83 Process 1.81 or 1.82 further comprising first converting        the compound of Formula VII to a compound of Formula IX

-   -   -   wherein R³⁰ is as defined above.

    -   1.84 Process 1.83 wherein Formula IX is formed by reaction with        a compound comprising P or S.

    -   1.85 Process 1.84 wherein Formula IX is formed by reaction with        PCl₃, PCl₅, or SOCl₂.

    -   1.86 Process 1.82-1.85 wherein the reaction occurs in a nonpolar        solvent.

    -   1.87 Process 1.86 wherein the nonpolar solvent is toluene.

    -   1.88 Process 1.82-1.87 wherein the reaction is heated to reflux.

    -   1.89 Process 1.82-1.88 wherein the reaction is stirred for about        12 hours.

    -   1.90 Process I or 1.1-1.89 wherein the process is as depicted        below:

-   -   -   wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R³⁰, R³¹, R³², R³³, R³⁴,            R³⁵, and R³⁶ are as defined above.

    -   1.91 Process I or 1.1-1.90 wherein the process is as depicted        below:

-   -   -   wherein R⁶ and R⁷ are as defined above.

    -   1.92 Process I or 1.1-1.91 wherein the process is as depicted        below:

-   -   -   wherein R⁶ and R⁷ are as defined above.

    -   1.93 Process I or 1.1-1.92 further comprising isolating the        compound of Formula I, e.g., the compound of formula 1.1-1.52.

As used throughout, ranges are used as shorthand for describing each andevery value that is within the range. Any value within the range can beselected as the terminus of the range. In addition, all references citedherein are hereby incorporated by referenced in their entireties. In theevent of a conflict in a definition in the present disclosure and thatof a cited reference, the present disclosure controls.

EXAMPLES

The synthetic methods for various compounds of Formula I are illustratedbelow. The intermediates of compounds of Formula I as well as othercompounds of Formula I may be made using the methods as similarlydescribed below and/or by methods similar to those generally describedin the detailed description and by methods known in the chemical art.

Terms and Abbreviations

DMAP=4-(dimethylamino)pyridine

Hünig's base=N,N-diisopropylethylamine

TFA=trifluoroacetic acid

Example 1 2-{[3,5-Bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyldihydrogen phosphate

Step 1: N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide(Compound 1)

5-chloro salicylic acid (8.75 g, 50 mmol, 1 eq) is dissolved in toluene(300 mL) under N₂ atmosphere then phosphorus trichloride (2.2 mL, 25mmol, 0.5 eq) is added dropwise followed by3,5-bis(trifluoromethyl)aniline (10 g, 43.7 mmol, 0.87 eq). The reactionmixture is stirred under reflux for 12 h then cooled to roomtemperature. The reaction mixture is quenched with NaHCO₃ saturatedsolution and stirred for 10 min. To this solution is added 1M HCl (100mL) until the pH of the aqueous layer is 5 and the aqueous layer isextracted with ethyl acetate (2×300 mL). The combined organics are thendried over sodium sulfate and concentrated in vacuo to yield the crudeproduct which is purified by flash chromatography (5-20% EtOAc/hex). Theyield of pure product as a white solid is 16 g (yield 85%) which is >95%pure by ¹H NMR. ¹H NMR (400 MHz, CDCl₃): δ 11.35 (bs, 1H), 10.85 (bs,1H), 8.40 (s, 2H), 7.80-7.79 (m, 2H), 7.50 (dd, 1H), 7.00 (d, 1H).

Step 2: 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenylbis(2-(trimethylsilyl)ethyl) phosphate

N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (4.0 g,0.01 mol, 1 eq) is dissolved in CH₃CN (104 mL) then DMAP (0.08 g, 0.001mol, 0.06 eq), Hunig's base (7.36 mL, 0.021 mol, 2 eq) and CCl₄ (8.02 g,0.052 mol, 5 eq) are added in this order. The solution is cooled to 0°C. and the HP(O)(OCH₂CH₂Si(CH₃)₃)₂ (4.66 g, 0.016 mol, 1.5 eq) in CH₃CN(5 mL) is added dropwise. The reaction mixture is stirred at roomtemperature for 20 h then water is added and extracted twice with EtOAc.The combined organic layers are washed with a saturated solution ofNaCl, dried over Na₂SO₄, filtered and the solvent is concentrated invacuo to give the crude material which is used as such for next step. ¹HNMR (200 MHz, CDCl₃): δ 10.20 (bs, 1H), 8.32 (s, 2H), 7.90 (s, 1H), 7.62(s, 1H), 7.45-7.40 (m, 1H), 7.30-7.28 (m, 1H), 4.40-4.30 (m, 4H),1.20-1.00 (m, 4H), 0.0 (s, 18H).

Step 3: 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenylDihydrogen Phosphate

2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenylbis(2-(trimethylsilyl)ethyl) phosphate (6.64 g, 0.01 mol, 1 eq) isdissolved in a mixture TFA:Water (5:1, 50 mL). The reaction mixture isstirred at room temperature for 2 h then solvent is concentrated invacuo. The resulting white solid is dissolved in Et₂O (20 mL) thenconcentrated in vacuo. This operation is repeated twice or until thecompound becomes much less soluble in Et₂O. The resulting material issuspended in a mixture Et₂O:Hex (6:1, 50 mL) and filtered to give thedesire material as light red solid. Finally, the solid is dissolved inwater (100 mL), filtered and the resulting aqueous solution is freezedried to give the desired product as a white solid (yield 76% over twosteps, 97% pure by HPLC). ¹H NMR (400 MHz, CD₃OD): δ 8.38 (s, 2H), 7.78(s, 1H), 7.70 (s, 1H), 7.55-7.50 (m, 1H), 7.45-7.43 (m, 1H).

Example 2 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenylPhosphate Bis Ethanolamine Salt

2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogenphosphate (2.14 g, 0.005 mol, 1 eq) is dissolved in MeOH (46 mL) thenethanolamine (0.56 mL, 0.009 mol, 2 eq) is added. The reaction mixtureis stirred at room temperature for 2 h then solvent is concentrated invacuo to give the desired product as a white solid (yield 84%, 97% pureby HPLC). ¹H NMR (300 MHz, D₂O): δ 8.15 (s, 2H), 7.85 (d, 2H), 7.37-7.34(m, 2H), 3.62 (t, 4H), 2.95 (t, 4H).

Example 3 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenylPhosphate Bis Diethanolamine Salt

2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogenphosphate (300 mg, 0.647 mmol, 1 eq) is dissolved in MeOH (3.2 mL) thendiethanolamine (0.124 mL, 1.294 mmol, 2 eq) is added. The reactionmixture is stirred at room temperature for 2 h then solvent isconcentrated in vacuo to give the desire product as a yellow foam (yield100%, 95% pure by HPLC). ¹H NMR (500 MHz, DMSO-d₆): δ 8.52 (s, 2H), 7.76(s, 1H), 7.62 (s, 1H), 7.48 (d, 1H), 7.37 (d, 1H), 3.55 (s, 8H), 2.80(s, 8H).

Example 4 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenylPhosphate Bis Triethanolamine Salt

2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogenphosphate (300 mg, 0.647 mmol, 1 eq) is dissolved in MeOH (3.2 mL) thentriethanolamine (0.172 mL, 1.294 mmol, 2 eq) is added. The reactionmixture is stirred at room temperature for 2 h then solvent isconcentrated in vacuo to give the desired product as a yellow oil (yield100%, 98% pure by HPLC). ¹H NMR (500 MHz, DMSO-d₆): δ 8.50 (s, 2H), 7.76(s, 1H), 7.62 (s, 1H), 7.52 (d, 1H), 7.29 (d, 1H), 3.55 (s, 12H), 2.82(s, 12H).

Example 5 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenylPhosphate Bis Sodium Salt

2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogenphosphate (300 mg, 0.647 mmol, 1 eq) is suspended in water (6.4 mL) thenNaOH (1M) (1.29 mL, 1.294 mmol, 2 eq) is added. The reaction mixture isstirred at room temperature for 2 h then the solution is filtered andfreeze dried to give the desired product as a white solid (yield 100%,93% pure by HPLC).

Example 6 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenylPhosphate Bis Potassium Salt

2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogenphosphate (300 mg, 0.647 mmol, 1 eq) is suspended in water (6.4 mL) thenKOH (1M) (1.29 mL, 1.294 mmol, 2 eq) is added. The reaction mixture isstirred at room temperature for 2 h then the solution is filtered andfreeze dried to give the desired product as a white solid (yield 100%,82% pure by HPLC).

Example 7 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenylHydrogen Phosphate Mono Sodium Salt,2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl HydrogenPhosphate Bis Sodium Salt, and2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl HydrogenPhosphate Bis Ethanolamine Salt

2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl hydrogenphosphate mono sodium salt,2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl phosphatebis sodium salt, and2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl phosphatebis ethanolamine salt are made as follows: 2 mM of2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogenphosphate is dissolved in ethanol 50 ml and appropriate equivalents ofeach base are added. Evaporation gives salts which are dissolved inwater and freeze dried.

Example 8 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenylPhosphate Mono Ethanolamine Salt (Compound 2.19)

2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl hydrogenphosphate mono ethanolamine salt is made as follows: 1 g of2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogenphosphate is dissolved in isopropanol and 1 eq ethanol amine is added.Evaporation gave2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl hydrogenphosphate mono ethanolamine salt.

Example 9 Stability and Solubility

To understand the stability and solubility of the novel prodrug salts a95% pure lot of2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogenphosphate is purified as follows. 15 g is dissolved in 1.2 L of waterwith 120 mM of sodium hydroxide and extracted with 500 ml ethyl acetateto remove phenol and non acid impurities. The aqueous layer is acidifiedwith concentrated HCl to pH 1.2 and extracted with ethyl acetate 1 Lfollowed by 600 ml. The ethyl acetate layer is dried MgSO₄ and sodiumsulphate, filtered, and evaporated to give about 13 g of 98% pure2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogenphosphate. NMR showed 1 mole of ethyl acetate trapped in solid. Ethylacetate is removed by adding 100 ml of methanol and evaporating.2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogenphosphate is stable at RT for a week or more. Sample kept at RT. It issoluble at 5 mg/mL in 1% Na₂HPO₄ giving pH of about 7. Dissolved in 2%Na₂HPO₄ at 5 mg/mL gives pH of 7.4

2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl hydrogenphosphate mono sodium salt (“mono sodium salt”),2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl phosphatebis sodium salt (“bis sodium salt”), and2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl phosphatebis ethanolamine salt (“bis ethanolamine salt”) are made and freezedried as in Example 7. In all cases stability studies show hydrolysis inthe solid state at about 1% per day. Solubilities are about 5 mg/mL formono sodium salt and 10 mg/mL for both bis sodium and bis ethanolaminesalt in water.

Final pH of solutions are about 7.5 for the bis ethanolamine salt, pH8.5 for mono sodium salt, and pH 9.5 for bis sodium salt in water. Inall cases solutions of these salts show less than 1% phenol over 12 hrs.Longer term their stability is the same as the solid samples (about 1%per day at RT). Hydrolysis rate is expected to be faster at higher pH.

2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl phosphatemono ethanolamine salt (“mono ethanolamine salt”) is made as in Example8. Surprisingly, the mono ethanolamine salt only shows about 1%hydrolysis after 5 days at RT. Its solubility in water is about 5 mg/ml.Solubility is expected to be higher at higher pH.

Example 10—Phenylbenzamide-AQP Structure-Activity Relationship

Structure activity relationships (SARs) are determined by assayinganalogues of selected hits to guide chemistry for the preparation of newmolecules to be tested for improved potency. For this iterative processwe use a quantitative kinetic assay—the Aquaporin-Mediated Cell VolumeChange Assa—in a 96-well multiplate reader. It detects changes in lightscattering by a monolayer of CHO cells expressing the desired AQP asthey shrink when exposed to hypertonic solution (300 mOsm→530 mOsm).FIG. 1 depicts the aquaporin-mediated cell volume change assay with AQP4expressing cells (FIG. 1A) and AQP2 expressing cells (FIG. 1B). Thecells expressing aquaporins shrink more rapidly than control cells, dueto enhanced water flow, which shrinkage can be inhibited by a compoundthat inhibits the aquaporin.

In FIG. 1, aquaporin-expressing cells are shown in the presence of DMSO(triangles) or in the presence of the test compound (here, Compound 3)at 10 μM (squares), along with CHO-CD81 expressing control cells in thepresence of DMSO (diamonds). Each curve represents an average of 16wells in the 96-well plate.

In FIG. 1A, when the AQP4b cells treated with DMSO are exposed tohypertonic shock, the cells show rapid shrinking, giving a rise in lightscattering (increasing relative change in absorbance, Abs/Abs₀) followedby a decay as cells detach from the plate. The CHO-AQP4b cell line showsa 4.5-fold increase in the rate of shrinking compared to CHO-CD81control cells (fitted to a double exponential model). CHO-AQP4b cellstreated with the Compound 3 analogue at 10 μM (squares) show a slowerrate of shrinking (55% inhibition) as seen by characteristic ‘unbending’of the light scattering curve. Similarly, FIG. 1B depicts an experimentcomparing CHO-AQP2 treated with DMSO or with Compound 3 at 10 μM.Aquaporin-2 has a lower intrinsic water permeability than AQP4 asobserved here. CHO-AQP2 cell lines treated with DMSO (FIG. 1B,triangles) show a 1.7-fold increase in the rate of shrinking compared toCHO-CD81 control cells (diamonds) also treated with DMSO (fitted to adouble exponential model) (FIG. 1B). CHO-AQP2 cells treated withCompound 3 at 10 μM (squares) show a slower rate of shrinking (81%inhibition), when comparing the relative change in Abs (Abs/Abs₀) (FIG.1B).

The data indicates that in this assay, Compound 3 is capable ofsignificantly inhibiting AQP2 and AQP4 activity, e.g. by greater than50%, at concentrations of 10 μM.

Example 11—Aquaporin Specificity of the Phenylbenzamide Compounds

The specificity of the compounds is tested against the most closelyrelated of the 13 known aquaporins: AQP1, AQP2, AQP5 and both splicevariants of AQP4 (A and B). A stable CHO cell line is created for eachof the above aquaporins and the inhibition of water permeability usingthe Aquaporin-Mediated Cell Volume Change Assay with 10 μM Compound 3 istested. Compound 3 inhibits AQP2 and 4, while it poorly inhibits AQP1and 5 (FIG. 2).

Example 12—Direct Drug-Target Interactions Between Phenylbenzamides andAQP4

To support the mechanism of action by which phenylbenzamides directlyblock AQP4, we perform in vitro binding studies using purified AQP4b andCompound 4 radiolabeled with ³H. Using a Hummel-Dryer style assay, a gelfiltration column is equilibratrated with buffer containing detergent,to maintain solubility of AQP4b, and 1 μM [³H]-Compound 4. AQP4b isdiluted to 250 μM in this column buffer and incubated at RT for 30 min.The sample is then applied to the column, fractions collected and thepresence of [³H]-Compound 4 detected by liquid scintillation counting.FIG. 3 shows the elution profile of [³H]-Compound 4 from the gelfiltration column with the elution positions of tetrameric and monomericAQP4b indicated. The rise in [³H]-Compound 4 from a baseline value of 1μM represents binding to each of these proteins. Although no monomericAQP4b can be readily detected in our highly purified AQP4b byconventional means, this assay reveals the presence of a small, albeitvanishing, amount of monomer. The relative affinities for Compound 4 are˜100 μM and less than 1 μM for tetramer and monomer, respectively. Thisassay shows relatively weak binding of Compound 4 to solubilized AQP4b;nevertheless, it clearly demonstrates that this phenylbenzamide directlyinteracts with AQP4b.

Example 13—Pharmacological Proof-of-Concept

Mouse Water Toxicity Model—Survival Curves: The in vivo efficacies ofthe compounds are tested using the mouse water toxicity model, where amouse is injected with water at 20% of its body weight. Manley, G. T. etal. Aquaporin-4 deletion in mice reduces brain edema after acute waterintoxication and ischemic stroke. Nat Med 6, 159-163 (2000); Gullans, S.R. & Verbalis, J. G. Control of brain volume during hyperosmolar andhypoosmolar conditions. Annual Review of Medicine 44, 289-301 (1993).The resulting euvolemic hyponatremia rapidly leads to CE, making this apractical model to test an inhibitor of the CNS aquaporin, AQP4b.

The ability of mice to survive H₂O toxicity is determined in threeexperiments using 10-12 mice each (16-19 weak old male/female).Deionized water is prepared for injection with either 0.39 mg/kgphenylbenzamide (placebo) or 0.76 mg/kg with test compound. FIG. 4 showsthe combined results of these experiments (n=33 placebo, n=34 Compound1). Percent survival of the Compound 1 cohorts improves 3.2 fold and thetime to 50% survival for animals treated with Compound 1 is improved byroughly 52 min.

Mouse Water Toxicity Model—Brain Volume by Magnetic Resonance Imaging(MRI): MRI is used to measure changes in brain volume in response towater shock, using the water toxicity model. As described for thesurvival and brain water content studies above, mice are injected, IP,with a water bolus alone or water bolus and test compound at 0.76 mg/kg,and changes in brain volume as detected by MRI are monitored. Mousebrain volumes are assessed using MRI scans collected with a 9.4T BrukerBiospec MRI scanner at the Case Center for Imaging Research at CaseWestern Reserve University. This imaging method is found to providesufficient contrast and resolution to sensitively detect changes intotal brain volume in the mouse water toxicity model for cerebral edema.High resolution T2-weighted sagittal scans (resolution=0.1 mm×0.1 mm×0.7mm) of the mouse head are obtained prior to water injection, 5.67 minpost water injection, and then every 5.2 minutes until the animalexpires from the water loading. Each scan contains twenty-five 0.7 mmcontiguous imaging slices of which 14-15 slices contain a portion of thebrain. The cross sectional area of the brain in each imaging slice ismeasured by manual region-of-interest selection using ImageJ. Brainvolumes are then calculated for each scan by summing the individualcross sectional brain areas and multiplying by the slice thickness (0.7mm).

Treatment with Compound 1 at 0.76 mg/kg reduces the rate of CEdevelopment from 0.081 to 0.032 min⁻¹ (or 2.5-fold) fit to a singleexponential model (FIG. 5). Also, the extent of CE during the period ofobservation is reduced (FIG. 5). Moreover, plasma levels in the sameassay are found to range between 0.03-0.06 μg as determined by LC-MS/MS(performed at Lerner Center, Cleveland Clinic, Cleveland, Ohio) and aresufficient to show efficacy in this model for CE.

The brain volume by magnetic resonance imaging experiment is alsoconducted with phenylbenzamide (0.39 mg/kg) and Compound 4 (0.83 mg/kg).Compound 4 reduces the rate of CE development from 0.081 to 0.022 min⁻¹(Table 1). Phenylbenzamide fails to show reduction in the rate of CE inmice (Table 1).

TABLE 1 Efficacy of compounds on CE formation in the mouse watertoxicity model AQP Inhibition Cerebral Edema Cell-Based Rate by CompoundAssay (%) MRI (min⁻¹) No Drug 0 0.081 Compound 1 47.9 0.032Phenylbenzamide 4.5 0.096 Compound 4 38.9 0.022

For no drug and Compound 1, n=14 mice each. For phenylbenzamide andCompound 4, n=12 mice each.

Example 14—High Throughput Screening Assay

Under hypotonic shock, both untransfected cells and cells expressing anunrelated transmembrane protein (CD81, at levels equivalent to AQP4b)swell slowly but remain intact.

These observations are used to develop our high-throughput screeningassay (HTS).

After hypotonic shock in a 384 well plate format, we return osmolalityto normal (300 mOSM) by adding 2× concentrated phosphate buffered salinesupplemented to 2 μM with a nonfluorescent acetoxymethyl derivative ofcalcein (calcein-AM) to each well. Intact cells take up calcein-AM andconvert it to the fluorescent dye calcein giving a quantitative measureof the remaining intact cells. Burst cells do not convert the precursorto the dye. Water uptake by AQP4-expressing cells is relatively rapid,with most test cells bursting within 4 min of hypotonic shock, whereasmost cells expressing CD81 remain viable after 8 min. Intracellularconversion of calcein-AM provides a strong and easily detectable signalat 535 nM in our assay (FIG. 6).

Calcein fluorescence end-point assay: Cells are seeded 24 hr beforeassay to reach 100% confluence. Culture medium is replaced with H₂O for5:30 min (osmotic shock). Osmolality is then normalized with theaddition of 2×PBS plus 2 μM calcein-AM. Cells are then incubated at 37°C. for an additional 30 min and fluorescence measured on a plate-reader.Rows 1-22 are seeded with CHO-AQP4 cells, and rows 23-24, with CHO-CD81cells (384 well plate). Note, all plate edges are discarded. RelativeFluorescence Intensity is calculated as the fluorescence intensity (FI)of each well divided by the mean FI of AQP4 cells treated with DMSO(control). Criteria for a successful assay: coefficients of variation(CVs)<15%, and Z-factors >0.5. Statistical analysis shows that 5.5 minof osmotic shock provides the optimal signal-to-noise ratio.

TABLE 2 Statistics for endpoint ‘calcein’ assay in FIG. 6; 5:30 min timepoint shown: Mean StDev CV Z′ S/B AQP4 581618 66311 11% 0.629 5.0 CD812910106 221240  8%

As will be observed, the signal for the CD81 cells is ca. 5× higher thanthe signal for the APQ4 cells, because by 5.5 mins, most of the AQP4cells have burst, while most of the CD81 cells remain intact. Inhibitionof AQP4 would therefore be expected to provide a higher signal, morelike the CD81 cells.

This assay is applied in a pilot screen of the MicroSource GenPlus 960and the Maybridge Diversity™ 20 k libraries (approximately 21,000compounds tested, each compound at 10-20 μM).

From this assay, a specific chemical series is identified,phenylbenzamides, which represents 3 out of the top 234 hits.

Hits from the HTS are validated using the same assay using a differentplating arrangement. In FIG. 7, we show this validation assay used toexamine Compound 3. Cells are seeded in a 96 well multiplate format withthe plates edges omitted (lanes 1 and 24) and an entire column (n=16) isused to test the ability of a compound to block AQP4-mediated cellbursting upon H₂O shock. CHO cells expressing CD81 are seeded in lanes2-3 as a control, and CHO cells expressing AQP4, in lanes 4-23. Cellsare treated with 0.1% DMSO in 10% FBS, DMEM (even numbered columns) or10 μM Compound 1 (odd number columns) in 0.1% DMSO, 10% FBS, DMEM for 30minutes. The cells are shocked with H₂O for 5:30 minutes, thenosmolality returned to 300 mOSM in the presence of 1 μM calcein-AM, asdescribed above. The cells are incubated at 37° C. for 30 minutes andthe relative fluorescence measured (ex 495/em 535 nM) on a fluorescencemultiplate reader. The data in FIG. 7 represents the average relativefluoresence units (RFU±SEM, n=16).

Example 15—Water Toxicity Model for CE: Intracranial Pressure (ICP)

ICP is monitored using a Samba 420 Sensor, pressure transducer, with aSamba 202 control unit (Harvard Apparatus, Holliston, Mass.). This ICPmonitoring system consists of a 0.42 mm silicon sensor element mountedon an optical fiber. A 20-gauge syringe needle is implanted through thecisterna magna to a depth of ˜1 cm. The needle then acts as a guide forinsertion of the Samba Sensor and the site of implantation and the openend of the needle are sealed with 100% silicone sealant. A baseline ICPreading is established followed by a water bolus IP injection (20%weight of animal) with or without Compound 1. ICP is monitored until theanimal expires from the water load.

Adjusting for the slight rise in ICP observed in the animals when theyare monitored without the water bolus injection (FIG. 8, No WaterToxicity), Compound 1 at 0.76 mg/kg reduces the relative rate of ICPrise by 36%, from 3.6×10⁻³ min⁻¹ to 2.3×10⁻³ min⁻¹ (n=6 mice/treatment,mean±SEM).

Example 16—Conversion of2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl PhosphateBis Ethanolamine Salt to Compound 1

Plasma or serum levels of Compound 1 are measured by LC-MS/MS at theMass Spectrometry II Core facility at the Lemer Research Institute ofthe Cleveland Clinic Foundation. Measurements are taken at 15 minutesand 24 hours after a 10 mg/kg i.p. loading dose and 1 mg/ml at 8 μl/hmaintenance dose (delivered by an Alzet i.p. osmotic pump, Durect Corp.,Cupertino, Calif.) of2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl phosphatebis ethanolamine salt (n=5 mice/time point, mean±SEM) (FIG. 9). Afterinitial processing to remove proteins (75% acetonitrile extraction),Compound 3 is introduced to improve quantitation using multiple reactionmonitoring (MRM). Samples are analyzed by tandem LC-MS/MS using C18reversed-phase chromatography and mass analysis with a triple-quadrapolemass spectrometer. The LC method is sufficient to separate Compound 1from Compound 3 and subsequent MRM gave reliable quantitation with alinear response from 0.004-0.4 ng of Compound 1 for its most abundantdaughter ion. The dashed line in FIG. 9 is the relative effective plasmaconcentration of Compound 1 observed in the mouse water toxicity model.Inclusion of an Alzet osmotic pump (Durect Corp., Cupertino, Calif.)containing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenylphosphate bis ethanolamine salt in the peritoneum is sufficient, inconjunction with an initial loading dose, to sustain Compound 1 abovethe expected efficacious plasma concentration of 20 ng/ml for 24 hours(FIG. 9).

The solubility of Compound 1 in water is 3.8 μg/ml. The solubility ofCompound 5 in water is 1 mg/ml.

Initial experiments show rapid bioconversion of2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl phosphatebis ethanolamine to Compound 1 when added to mouse plasma in vitro. Lessthan 5 minutes at 20° C. is sufficient to render2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl phosphatebis ethanolamine undetectable. In addition,2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl phosphatebis ethanolamine salt is undetectable in plasma samples taken from miceinjected IP with2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl phosphatemono ethanolamine. Instead, Compound 1 is detected at a concentrationconsistent with good bioavailability and near-complete conversion of2-{([3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl phosphatebis ethanolamine. With2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl phosphatebis ethanolamine, doses of 10 mg/kg and IP injection volumes in saline(0.5 ml for a 30 g mouse), that give serum concentrations of Compound 1in excess of 400 ng/ml (FIG. 9) can be used. Key PK parameters for are:rate of absorption 0.12 min⁻¹; rate of elimination 0.017 min⁻.

Example 17 Animal Stroke Model

Most ischemic strokes (˜80%) occur in the region of the middle cerebralartery (MCA). To mimic this injury in mice, an intraluminal monofilamentmodel of middle cerebral artery occlusion (MCAo) is used. Occlusion isachieved by inserting a surgical filament into the external carotidartery (ECA) and threading it forward into the internal carotid artery(ICA) until the tip blocks the origin of the MCA. The resultingcessation of blood flow gives rise to subsequent brain infarction in theMCA territory (Longa, E. Z. et al., Reversible Middle Cerebral ArteryOcclusion Without Craniectomy in Rats, Stroke, 20, 84-91 (1989)). Thistechnique is used to study a temporary occlusion in which the MCA isblocked for one hour. The filament is then removed allowing reperfusionto occur for 24 hours before the animals brain is imaged usingT2-weighted scans in a 9.4T Bruker MRI scanner at the Case Center forImaging Research (FIG. 10). FIG. 10 shows a single slice from aT2-weighted MR image depicting the center of the brain showing cerebralcortex, hippocampus, thalamus, amygdala and hypothalamus for a “Normal”mouse (left panels) and a mouse which receives MCAo for one hourfollowed by 24 hours of reperfusion (right panels). Dashed lines markthe midline of the brain and show a large shift in the MCAo brain due tocerebral edema. Solid line highlights the region of infarct in the MCAobrain.

Survival—Mice are treated with Compound 5 using a 2 mg/kg i.p. loadingdose and 1 mg/ml at 8 μl/h maintenance dose (delivered by an i.p.osmotic pump) of Compound 5, or given saline (controls; n=17) using anidentical approach. In this model, we observed a 29.4% improvement inoverall survival at 24 h when animals are treated with Compound 5(X²(1)=4.26; P<0.05).

Cerebral Edema—Mice are given saline or treated with Compound 5 bymulti-dosing at 5 mg/kg i.p. every three hours (n=8 per treatment). Thisdosing regimen is sufficient to maintain a plasma concentration ofCompound 1>20 ng/ml for the duration of the study. Ipsilateral andcontralateral hemispheric volume is measured from the T2-weighted MRimages of mice 24 hours post-icus. Relative change in hemispheric volumeis calculated as a percent of the difference between ipsilateral brainvolume (V_(i)) and contralateral brain volume (V_(c)) relative to thecontralateral brain volume (Percent Change in Hemispheric BrainVolume=((V_(i)−V_(c))/V_(c))×100%.

Control animals show swelling in the ipsilateral hemisphere with arelative change in ipsilatcral brain volume of 13.4%+1.9%, while animalsgiven Compound 5 show a 4.2±1.7% change (P=0.003, ±SEM, see FIG. 11).This represents a 3.2-fold reduction in brain swelling after MCAo.

Neurological Outcome—In the same experiment as above, animals are scoredfor neurological outcome on a simple 5 point scale described in Manley,G. T. et al., Aquaporin-4 Deletion in Mice Reduces Brain Edema AfterAcute Water Intoxication and Ischemic Stroke, Nature Medicine, 6,159-163 (2000). An improvement in neurological outcome is observed foranimals given Compound 5. Control animals have an average neurologicalscore of 2.77±0.66, while animals given Compound 5 have an average scoreof 0.88±0.31 (FIG. 12, inset, P=0.025, n=9 per treatment). Animals givenCompound 5 did not progress into a state of severe paralysis or death.

The data from the MCAo stroke model together with the water toxicity(brain edema) model link the pharmacology of Compound 5/Compound 1 withimproved outcomes in stroke.

The invention claimed is:
 1. A process for synthesizing a compound ofFormula IV

wherein R¹, R², R³, R⁴, and R⁵ are independently H, halogen, C₁₋₄-alkyl,C₁₋₄-haloalkyl, or cyano, wherein the process comprises reacting acompound of Formula VII and a compound of Formula VIII

wherein R³⁰, R³¹, R³², R³³, and R³⁴ are independently H, halogen,C₁₋₄-alkyl, C₁₋₄-haloalkyl, or cyano to provide a compound of Formula V

wherein R³⁰, R³¹, R³², R³³, and R³⁴ are independently H, halogen,C₁₋₄-alkyl, C₁₋₄-haloalkyl, or cyano, followed by reacting the compoundof Formula V with a compound of Formula VI

wherein R³⁵ and R³⁶ are independently —(CH₂CH₂)_(n)—Si(R³⁷)₃ and eachR³⁷ is independently C₁₋₆-alkyl and n is 0 or 1 to provide a compound ofFormula III

wherein R³⁰, R³¹, R³², R³³, and R³⁴ are independently H, halogen,C₁₋₄-alkyl, C₁₋₄-haloalkyl, or cyano, R³⁵ and R³⁶ are independently—(CH₂CH₂)_(n)—Si(R³⁷)₃, and each R³⁷ is independently C₁₋₆-alkyl and nis 0 or 1, followed by deprotecting the compound of Formula III toproduce the compound of Formula IV.
 2. The process of claim 1, whereinthe process further comprises converting the compound of Formula VII toa compound of Formula IX

wherein R³⁰ is H, halogen, C₁₋₄-alkyl, C₁₋₄-haloalkyl, or cyano.
 3. Theprocess of claim 2, wherein the compound of Formula IX is formed byreaction with a compound comprising P or S.
 4. The process of claim 3,wherein the compound of Formula IX is formed by reaction with PCl₃,PCl₅, or SOCl₂.
 5. The process of claim 4, wherein the reaction occursin a nonpolar solvent.
 6. The process of claim 5, wherein the nonpolarsolvent is toluene.
 7. The process of claim 2, wherein R³⁰, R³², and R³⁴are independently halogen or C₁₋₄-haloalkyl and R³¹ and R³³ are H. 8.The process of claim 2, wherein R³⁰, R³², and R³⁴ are independently F,Cl, Br, or —CF₃ and R³¹ and R³³ are H.
 9. The process of claim 2,wherein R³⁰ is halogen, R³¹ and R³³ are H, and R³² and R³⁴ areindependently C₁₋₄-haloalkyl.
 10. The process of claim 9, wherein R³⁰ isCl and R³² and R³⁴ are —CF₃.
 11. The process of claim 2, wherein eachR³⁷ is independently C₁₋₄-alkyl.
 12. The process of claim 2, wherein R³⁵and R³⁶ are the same.
 13. The process of claim 2, wherein n is
 1. 14.The process of claim 10, wherein R³⁵ and R³⁶ are —CH₂—CH₂—Si(CH₃)₃. 15.The process of claim 14, wherein the compound of Formula V is


16. The process of claim 15, wherein the compound of Formula VI is


17. The process of claim 16, wherein the compound of Formula III is


18. The process of claim 17, wherein the compound of Formula III isdeprotected with a deprotecting agent comprising F.
 19. The process ofclaim 18, wherein the deprotecting agent is CF₃COOH.
 20. The process ofclaim 19, wherein the compound of Formula IV is